Skip to main content
SpringerLink
Log in

Rickets: The Skeletal Disorders of Impaired Calcium or Phosphate Availability

  • Chapter
  • First Online:
Pediatric Endocrinology

Abstract

Rickets derives from the old English word “wrikken” meaning to twist or bend and refers to conditions of impaired mineralization of growing bones, ultimately resulting in their bowing and twisting. Rickets and osteomalacia refer to similar processes occurring in different compartments of the bone. Rickets is evident histologically and radiographically as a disorganized and expanded growth plate (physis) of the growing bone, together with the accompanying osteomalacia (accumulation of excess unmineralized osteoid matrix due to a delayed mineral apposition rate) of the trabecular and cortical bone. Children with untreated rickets may develop severe curvature deformities of the lower extremities, primarily due to the effect of weight bearing on an under-mineralized skeleton. This chapter will describe the pathophysiology and clinical diagnostic and treatment approach to rickets from a variety of calciopenic and phosphopenic causes.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Crabtree NJ, Arabi A, Bachrach LK, Fewtrell M, El-Hajj Fuleihan G, Kecskemethy HH, et al. Dual-energy X-ray absorptiometry interpretation and reporting in children and adolescents: the revised 2013 ISCD pediatric official positions. J Clin Densitom. 2014;17(2):225–42.

    Article  PubMed  Google Scholar 

  2. Reid IR, Murphy WA, Hardy DC, Teitelbaum SL, Bergfeld MA, Whyte MP. X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry. Am J Med. 1991;90(1):63–9.

    Article  CAS  PubMed  Google Scholar 

  3. Demay MB, Sabbagh Y, Carpenter TO. Calcium and vitamin D: what is known about the effects on growing bone. Pediatrics. 2007;119(Suppl 2):S141–4.

    Article  PubMed  Google Scholar 

  4. Mayne PD, Kovar IZ. Calcium and phosphorus metabolism in the premature infant. Ann Clin Biochem. 1991;28(Pt 2):131–42.

    Article  CAS  PubMed  Google Scholar 

  5. Buchacz K, Brooks JT, Tong T, Moorman AC, Baker RK, Holmberg SD, et al. Evaluation of hypophosphataemia in tenofovir disoproxil fumarate (TDF)-exposed and TDF-unexposed HIV-infected out-patients receiving highly active antiretroviral therapy. HIV Med. 2006;7(7):451–6.

    Article  CAS  PubMed  Google Scholar 

  6. Kreiter SR, Schwartz RP, Kirkman HN Jr, Charlton PA, Calikoglu AS, Davenport ML. Nutritional rickets in African American breast-fed infants. J Pediatr. 2000;137(2):153–7.

    Article  CAS  PubMed  Google Scholar 

  7. Thacher TD, Abrams SA. Relationship of calcium absorption with 25(OH)D and calcium intake in children with rickets. Nutr Rev. 2010;68(11):682–8.

    Article  PubMed  Google Scholar 

  8. Prentice A, Ceesay M, Nigdikar S, Allen SJ, Pettifor JM. FGF23 is elevated in Gambian children with rickets. Bone. 2008;42(4):788–97.

    Article  CAS  PubMed  Google Scholar 

  9. Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular basis of vitamin D-dependent rickets type I. Endocr J. 2001;48(4):427–32.

    Article  CAS  PubMed  Google Scholar 

  10. Glorieux FH, St-Arnaud R. Molecular cloning of (25-OH D)-1 alpha-hydroxylase: an approach to the understanding of vitamin D pseudo-deficiency. Recent Prog Horm Res. 1998;53:341–50.

    CAS  PubMed  Google Scholar 

  11. Thacher TD, Levine MA. CYP2R1 mutations causing vitamin D-deficiency rickets. J Steroid Biochem Mol Biol. 2017;173:333–36.

    Article  CAS  PubMed  Google Scholar 

  12. Al Mutair AN, Nasrat GH, Russell DW. Mutation of the CYP2R1 vitamin D 25-hydroxylase in a Saudi Arabian family with severe vitamin D deficiency. J Clin Endocrinol Metab. 2012;97(10):E2022–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev. 1999;20(2):156–88.

    CAS  PubMed  Google Scholar 

  14. Chen CH, Sakai Y, Demay MB. Targeting expression of the human vitamin D receptor to the keratinocytes of vitamin D receptor null mice prevents alopecia. Endocrinology. 2001;142(12):5386–9.

    Article  CAS  PubMed  Google Scholar 

  15. Econs MJ, Samsa GP, Monger M, Drezner MK, Feussner JR. X-linked hypophosphatemic rickets: a disease often unknown to affected patients. Bone Miner. 1994;24:17–24.

    Article  CAS  PubMed  Google Scholar 

  16. Nehgme R, Fahey JT, Smith C, Carpenter TO. Cardiovascular abnormalities in patients with X-linked hypophosphatemia. J Clin Endocrinol Metab. 1997;82(8):2450–4.

    Article  CAS  PubMed  Google Scholar 

  17. Carpenter TO. New perspectives on the biology and treatment of X-linked hypophosphatemic rickets. Pediatr Clin N Am. 1997;44(2):443–66.

    Article  CAS  Google Scholar 

  18. Hyp Consortium. A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. The HYP Consortium. Nat Genet. 1995;11(2):130–6.

    Article  Google Scholar 

  19. Liu S, Guo R, Simpson LG, Xiao Z-S, Burnham CE, Quarles LD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003;278(39):37419–26.

    Article  CAS  PubMed  Google Scholar 

  20. Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, et al. Polypeptide GaINAc-transferase T3 and familial tumoral calcinosis: secretion of FGF23 requires O-glycosylation. J Biol Chem. 2006;281(27):18370–7.

    Article  CAS  PubMed  Google Scholar 

  21. Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770–4.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem. 2005;280(4):2543–9.

    Article  CAS  PubMed  Google Scholar 

  24. 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(11):1310–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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(2):273–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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(2):267–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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(4):379–81.

    Article  CAS  PubMed  Google Scholar 

  28. Rafaelsen SH, Ræder H, Fagerheim AK, Knappskog P, Carpenter TO, Johansson S, et al. Exome sequencing reveals FAM20c mutations associated with FGF23-related hypophosphatemia, dental anomalies and ectopic calcification. J Bone Miner Res. 2013;28(6):1378–85.

    Article  CAS  PubMed  Google Scholar 

  29. Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U S A. 2014;111(15):5520–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. ADHR_Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345–8.

    Article  CAS  Google Scholar 

  31. 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(6):2079–86.

    Article  CAS  PubMed  Google Scholar 

  32. Imel EA, Hui SL, Econs MJ. FGF23 concentrations vary with disease status in autosomal dominant hypophosphatemic rickets. J Bone Miner Res. 2007;22(4):520–6.

    Article  CAS  PubMed  Google Scholar 

  33. Econs MJ, McEnery PT. Autosomal dominant hypophosphatemic rickets/osteomalacia: clinical characterization of a novel renal phosphate-wasting disorder. J Clin Endocrinol Metab. 1997;82(2):674–81.

    Article  CAS  PubMed  Google Scholar 

  34. 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(46):1146–55.

    Article  CAS  Google Scholar 

  35. 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(11):3541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Imel EA, Gray A, Padgett L, Econs MJ. Iron and fibroblast growth factor 23 in X-linked hypophosphatemia. Bone. 2014;60:87–92.

    Article  CAS  PubMed  Google Scholar 

  37. Schouten BJ, Doogue MP, Soule SG, Hunt PJ. Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia. Ann Clin Biochem. 2009;46(Pt 2):167–9.

    Article  PubMed  Google Scholar 

  38. Schouten BJ, Hunt PJ, Livesey JH, Frampton CM, Soule SG. FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study. J Clin Endocrinol Metab. 2009;94(7):2332–7.

    Article  CAS  PubMed  Google Scholar 

  39. Shimizu Y, Tada Y, Yamauchi M, Okamoto T, Suzuki H, Ito N, et al. Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: another form of FGF23-related hypophosphatemia. Bone. 2009;45(4):814–6.

    Article  CAS  PubMed  Google Scholar 

  40. Wolf M, Koch TA, Bregman DB. Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women. J Bone Miner Res. 2013;28(8):1793–803.

    Article  CAS  PubMed  Google Scholar 

  41. Folpe A, Fanburg-Smith J, Billings S, Bisceglia M, Bertoni F, Cho J, 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):1–30.

    Article  PubMed  Google Scholar 

  42. Jan De Beur SM, Finnegan RB, Vassiliadis J, Cook B, Barberio D, Estes S, et al. Tumors associated with oncogenic osteomalacia express genes important in bone and mineral metabolism. J Bone Miner Res. 2002;17(6):1102–10.

    Article  CAS  Google Scholar 

  43. Carpenter TO, Ellis BK, Insogna KL, Philbrick WM, Sterpka J, Shimkets R. FGF7 – an inhibitor of phosphate transport derived from oncogenic osteomalacia-causing tumors. J Clin Endocrinol Metab. 2005;90(2):1012–20.

    Article  CAS  PubMed  Google Scholar 

  44. Imel EA, Peacock M, Pitukcheewanont P, Heller HJ, Ward LM, Shulman D, et al. Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia. J Clin Endocrinol Metab. 2006;91(6):2055–61.

    Article  CAS  PubMed  Google Scholar 

  45. Lee JC, Jeng YM, SY S, CT W, Tsai KS, Lee CH, et al. Identification of a novel FN1-FGFR1 genetic fusion as a frequent event in phosphaturic mesenchymal tumour. J Pathol. 2015;235(4):539–45.

    Article  CAS  PubMed  Google Scholar 

  46. Andreopoulou P, Dumitrescu CE, Kelly MH, Brillante BA, Peck CM, Wodajo FM, et al. Selective venous catheterization for the localization of phosphaturic mesenchymal tumors. J Bone Miner Res. 2011;26:1295–302.

    Article  PubMed  Google Scholar 

  47. Takeuchi Y, Suzuki H, Ogura S, Imai R, Yamazaki Y, Yamashita T, et al. Venous sampling for fibroblast growth factor-23 confirms preoperative diagnosis of tumor-induced osteomalacia. J Clin Endocrinol Metab. 2004;89(8):3979–82.

    Article  CAS  PubMed  Google Scholar 

  48. Imel EA, Econs MJ. Approach to the Hypophosphatemic patient. J Clin Endocrinol Metab. 2012;97(3):696–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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(5):683–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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(3):233–6.

    Article  PubMed  Google Scholar 

  51. Nafidi O, Lapointe RW, Lepage R, Kumar R, D’Amour P. Mechanisms of renal phosphate loss in liver resection-associated hypophosphatemia. Ann Surg. 2009;249(5):824–7.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Wasserman H, Ikomi C, Hafberg ET, Miethke AG, Bove KE, Backeljauw PF. Two case reports of FGF23-induced hypophosphatemia in childhood biliary atresia. Pediatrics. 2016;138(2):e20154453.

    Article  PubMed  Google Scholar 

  53. Prie D, Forand A, Francoz C, Elie C, Cohen I, Courbebaisse M, et al. Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PLoS One. 2013;8(6):e66182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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(2):193–201.

    Article  CAS  PubMed  Google Scholar 

  55. Ichikawa S, Sorenson AH, Imel EA, Friedman NE, Gertner JM, Econs MJ. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab. 2006;91(10):4022–7.

    Article  CAS  PubMed  Google Scholar 

  56. 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(2):179–92.

    Article  CAS  PubMed  Google Scholar 

  57. Jaureguiberry G, Carpenter TO, Forman S, Juppner H, Bergwitz C. A novel missense mutation in SLC34A3 that causes hereditary hypophosphatemic rickets with hypercalciuria in humans identifies threonine 137 as an important determinant of sodium-phosphate cotransport in NaPi-IIc. Am J Physiol Renal Physiol. 2008;295(2):F371–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dasgupta D, Wee MJ, Reyes M, Li Y, Simm PJ, Sharma A, et al. Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol. 2014;25(10):2366–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Magen D, Berger L, Coady MJ, Ilivitzki A, Militianu D, Tieder M, et al. A loss-of-function mutation in NaPi-IIa and renal Fanconi's syndrome. N Engl J Med. 2010;362(12):1102–9.

    Article  CAS  PubMed  Google Scholar 

  60. Scheinman SJ. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int. 1998;53(1):3–17.

    Article  CAS  PubMed  Google Scholar 

  61. Stechman MJ, Loh NY, Thakker RV. Genetic causes of hypercalciuric nephrolithiasis. Pediatr Nephrol. 2009;24(12):2321–32.

    Article  PubMed  Google Scholar 

  62. Gonzalez Ballesteros L, Ma N, Ward L, Backeljauw P, Weber D, DiMeglio L, et al. Hypophosphatemia associated with elemental formula use in children with feeding problems. Annual Meeting of the American Society for Bone and Mineral Research; October 9–12, 2015, Seattle, 2015. p. S433.

    Google Scholar 

  63. Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Ann N Y Acad Sci. 2011;1192:190–200.

    Article  CAS  Google Scholar 

  64. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904–13.

    Article  CAS  PubMed  Google Scholar 

  65. Warman ML, Abbott M, Apte SS, Hefferon T, McIntosh I, Cohn DH, et al. A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet. 1993;5(1):79–82.

    Article  CAS  PubMed  Google Scholar 

  66. Vega RA, Opalak C, Harshbarger RJ, Fearon JA, Ritter AM, Collins JJ, et al. Hypophosphatemic rickets and craniosynostosis: a multicenter case series. J Neurosurg Pediatr. 2016:17(6):694–700.

    PubMed  Google Scholar 

  67. 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(3):235–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fong H, Chu EY, Tompkins KA, Foster BL, Sitara D, Lanske B, et al. Aberrant cementum phenotype associated with the hypophosphatemic hyp mouse. J Periodontol. 2009;80(8):1348–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Walton RJ, Bijvoet OLM. Nomogram for derivation of renal threshold phosphate concentration. Lancet. 1975;306(7929):309–10.

    Article  Google Scholar 

  70. Brodehl J, Krause A, Hoyer PF. Assessment of maximal tubular phosphate reabsorption: comparison of direct measurement with the nomogram of Bijvoet. Pediatr Nephrol. 1988;2(2):183–9.

    Article  CAS  PubMed  Google Scholar 

  71. Stark H, Eisenstein B, Tieder M, Rachmel A, Alpert G. Direct measurement of TP/GFR: a simple and reliable parameter of renal phosphate handling. Nephron. 1986;44(2):125–8.

    Article  CAS  PubMed  Google Scholar 

  72. Alon U, Hellerstein S. Assessment and interpretation of the tubular threshold for phosphate in infants and children. Pediatr Nephrol. 1994;8(2):250–1.

    Article  CAS  PubMed  Google Scholar 

  73. So NP, Osorio AV, Simon SD, Alon US. Normal urinary calcium/creatinine ratios in African-American and Caucasian children. Pediatr Nephrol. 2001;16(2):133–9.

    Article  CAS  PubMed  Google Scholar 

  74. Wagner CL, Greer FR, The Section on Breastfeeding Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122(5):1142–52.

    Article  PubMed  Google Scholar 

  75. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–8.

    Article  CAS  PubMed  Google Scholar 

  76. Munns CF, Shaw N, Kiely M, Specker BL, Thacher TD, Ozono K, et al. Global consensus recommendations on prevention and management of nutritional rickets. Horm Res Paediatr. 2016;85(2):83–106.

    Article  CAS  PubMed  Google Scholar 

  77. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature. 1987;325(6099):62–5.

    Article  CAS  PubMed  Google Scholar 

  78. Thacher TD, Obadofin MO, O'Brien KO, Abrams SA. The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets. J Clin Endocrinol Metab. 2009;94(9):3314–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Isichei CO, Reading JC, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med. 1999;341(8):563–8.

    Article  CAS  PubMed  Google Scholar 

  80. Edouard T, Alos N, Chabot G, Roughley P, Glorieux FH, Rauch F. Short- and long-term outcome of patients with pseudo-vitamin D deficiency rickets treated with calcitriol. J Clin Endocrinol Metab. 2010;96:82–9.

    Article  PubMed  CAS  Google Scholar 

  81. Ma NS, Malloy PJ, Pitukcheewanont P, Dreimane D, Geffner ME, Feldman D. 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. 2009;45(4):743–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Balsan S, Garabedian M, Larchet M, Gorski AM, Cournot G, Tau C, 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. 1986;77(5):1661–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gutierrez OM, Mannstadt M, Isakova T, Rauh-Hain JA, Tamez H, Shah A, et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008;359(6):584–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cancela AL, Oliveira RB, Graciolli FG, Dos Reis LM, Barreto F, Barreto DV, et al. Fibroblast growth factor 23 in hemodialysis patients: effects of phosphate binder, calcitriol and calcium concentration in the dialysate. Nephron Clin Pract. 2010;117(1):c74–82.

    Article  PubMed  CAS  Google Scholar 

  85. Covic A, Passlick-Deetjen J, Kroczak M, Büschges-Seraphin B, Ghenu A, Ponce P, et al. A comparison of calcium acetate/magnesium carbonate and sevelamer-hydrochloride effects on fibroblast growth factor-23 and bone markers: post hoc evaluation from a controlled, randomized study. Nephrology Dialysis Transplantation. 2013;28(9):2383–92.

    Article  CAS  PubMed Central  Google Scholar 

  86. Block GA, Wheeler DC, Persky MS, Kestenbaum B, Ketteler M, Spiegel DM, et al. Effects of phosphate binders in moderate CKD. J Am Soc Nephrol. 2012;23(8):1407–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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(8):3591–7.

    Article  CAS  PubMed  Google Scholar 

  88. Glorieux FH, Marie PJ, Pettifor JM, Delvin EE. Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med. 1980;303(18):1023–31.

    Article  CAS  PubMed  Google Scholar 

  89. Harrell RM, Lyles KW, Harrelson JM, Friedman NE, Drezner MK. Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. J Clin Invest. 1985;75(6):1858–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician's guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381–8.

    Article  PubMed  PubMed Central  Google Scholar 

  91. 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(6):1378–83.

    CAS  PubMed  Google Scholar 

  92. Wilson DM. Growth hormone and hypophosphatemic rickets. J Pediatr Endocrinol Metab. 2000;13(Suppl 2):993–8.

    PubMed  Google Scholar 

  93. Makitie O, Toiviainen-Salo S, Marttinen E, Kaitila I, Sochett E, Sipila I. Metabolic control and growth during exclusive growth hormone treatment in X-linked hypophosphatemic rickets. Horm Res. 2008;69(4):212–20.

    PubMed  Google Scholar 

  94. Seikaly MG, Brown R, Baum M. The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics. 1997;100(5):879–84.

    Article  CAS  PubMed  Google Scholar 

  95. 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(3):395–402.

    Article  CAS  PubMed  Google Scholar 

  96. 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(8):610–3.

    Article  CAS  PubMed  Google Scholar 

  97. Zivicnjak M, Schnabel D, Staude H, Even G, Marx M, Beetz R, 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(12):E2097–105.

    Article  CAS  PubMed  Google Scholar 

  98. 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.

    Article  CAS  PubMed  Google Scholar 

  99. 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(4):1587–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Imel EA, Zhang X, Ruppe MD, Weber TJ, Klausner MA, Ito T, et al. Prolonged correction of serum phosphorus in adults with X-linked hypophosphatemia using monthly doses of KRN23. J Clin Endocrinol Metab. 2015;100(7):2565–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Carpenter T, Imel E, Boot A, Högler W, Linglart A, Padidela R, 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). Endocrine Society Annual Meeting ENDO 2016; Boston, 2016. p. Abstract OR14–13.

    Google Scholar 

  102. Connor J, Olear EA, Insogna KL, Katz L, Baker S, Kaur R, et al. Conventional therapy in adults with X-linked hypophosphatemia: effects on Enthesopathy and dental disease. J Clin Endocrinol Metab. 2015;100(10):3625–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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(9):3103–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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(3):658–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Raeder H, Bjerknes R, Shaw N, Netelenbos C. A case of X-linked hypophosphatemic rickets (XLH): complications and the therapeutic use of cinacalcet. Eur J Endocrinol. 2008. https://doi.org/10.1530/EJE-08-0383.

  106. 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.

    PubMed  PubMed Central  Google Scholar 

  107. Taylor A, Sherman NH, Norman ME. Nephrocalcinosis in X-linked hypophosphatemia: effect of treatment versus disease. Pediatr Nephrol. 1995;9(2):173–5.

    Article  CAS  PubMed  Google Scholar 

  108. 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(26):1843–8.

    Article  CAS  PubMed  Google Scholar 

  109. Eddy MC, McAlister WH, Whyte MP. X-linked hypophosphatemia: normal renal function despite medullary nephrocalcinosis 25 years after transient vitamin D2-induced renal azotemia. Bone. 1997;21(6):515–20.

    Article  CAS  PubMed  Google Scholar 

  110. Moltz KC, Friedman AH, Nehgme RA, Kleinman CS, Carpenter TO. Ectopic cardiac calcification associated with hyperparathyroidism in a boy with hypophosphatemic rickets. Curr Opin Pediatr. 2001;13(4):373–5.

    Article  CAS  PubMed  Google Scholar 

  111. 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 (Baltimore). 1989;68(6):336–52.

    Article  CAS  Google Scholar 

  112. Imel EA, Dimeglio LA, Hui SL, Carpenter TO, Econs MJ. Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab. 2010;95:1846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Carpenter TO, Insogna KL, Zhang JH, Ellis B, Nieman S, Simpson C, et al. Circulating levels of soluble klotho and FGF23 in X-linked hypophosphatemia: circadian variance, effects of treatment, and relationship to parathyroid status. J Clin Endocrinol Metab. 2010;95(11):E352–7.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Endo I, Fukumoto S, Ozono K, Namba N, Tanaka H, Inoue D, et al. Clinical usefulness of measurement of fibroblast growth factor 23 (FGF23) in hypophosphatemic patients proposal of diagnostic criteria using FGF23 measurement. Bone. 2008;42(6):1235–9.

    Article  CAS  PubMed  Google Scholar 

  115. Liu S, Tang W, Zhou J, Stubbs JR, Luo Q, Pi M, et al. Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol. 2006;17(5):1305–15.

    Article  CAS  PubMed  Google Scholar 

  116. Perwad F, Azam N, Zhang MY, Yamashita T, Tenenhouse HS, Portale AA. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinology. 2005;146(12):5358–64.

    Article  CAS  PubMed  Google Scholar 

  117. Watts L, Wordsworth P. Chiari malformation, syringomyelia and bulbar palsy in X linked hypophosphataemia. BMJ Case Rep 2015;2015. pii: bcr2015211961.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Caldemeyer KS, Boaz JC, Wappner RS, Moran CC, Smith RR, Quets JP. Chiari I malformation: association with hypophosphatemic rickets and MR imaging appearance. Radiology. 1995;195(3):733–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Internal Medicine and Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    Erik A. Imel MD

  2. Departments of Pediatrics and Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA

    Thomas O. Carpenter MD

Authors
  1. Erik A. Imel MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas O. Carpenter MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas O. Carpenter MD .

Editor information

Editors and Affiliations

  1. Department of Pediatrics, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

    Sally Radovick

  2. Pediatric Endocrinology, Massachusetts General Hospital for Children, Boston, Massachusetts, USA

    Madhusmita Misra

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Imel, E.A., Carpenter, T.O. (2018). Rickets: The Skeletal Disorders of Impaired Calcium or Phosphate Availability. In: Radovick, S., Misra, M. (eds) Pediatric Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-73782-9_23

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-73782-9_23

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-73781-2

  • Online ISBN: 978-3-319-73782-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation