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Hypophosphataemic Rickets: Diagnosis Algorithm—How Not to Make a Mistake

Abstract

Hypophosphataemic rickets is a heterogeneous group of entities characterized by rickets or osteomalacia due to a phosphate deficit caused mainly by decreased renal reabsorption. They are also characterized by defective intestinal absorption of calcium and rickets or osteomalacia unresponsive to cholecalciferol. These metabolic alterations lead to growth retardation, bone pain and deformities, and short stature. For a correct diagnosis and treatment of all forms of rickets, the basic aspects of pathophysiology of the calcium-phosphorus metabolism and the relevance of the bone-kidney axis modulated by the presence of phosphaturic agents need to be known. Diagnosis of these diseases includes clinical assessment, blood and urine analytical tests, and bone x-ray. The aim of this article is to briefly describe the pathophysiology, signs, symptoms, and clinical forms of hypophosphataemic rickets, proposing a diagnosis algorithm that can help in the clinical practice.

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References

  1. Negri AL. Hereditary hypophosphatemias: new genes in the bone-kidney axis. Nephrology (Carlton). 2007;12(4):317–20.

    CAS  PubMed  Article  Google Scholar 

  2. Shaikh A, Berndt T, Kumar R. Regulation of phosphate homeostasis by the phosphatonins and other novel mediators. Pediatr Nephrol. 2008;23(8):1203–10.

    PubMed  PubMed Central  Article  Google Scholar 

  3. Schiavi SC, Kumar R. The phosphatonin pathway: new insights in phosphate homeostasis. Kidney Int. 2004;65(1):1–14.

    CAS  PubMed  Article  Google Scholar 

  4. Alon US. Clinical practice. Fibroblast growth factor (FGF)23: a new hormone. Eur J Pediatr. 2011;170(5):545–54.

    CAS  PubMed  Article  Google Scholar 

  5. Mejia-Gaviria N, Gil-Peña H, Coto E, Pérez-Menéndez TM, Santos F. Genetic and clinical peculiarities in a new family with hereditary hypophosphatemic rickets with hypercalciuria: a case report. Orphanet J Rare Dis. 2010;5:1.

    PubMed  PubMed Central  Article  Google Scholar 

  6. 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.

    CAS  PubMed  Article  Google Scholar 

  7. Phulwani P, Bergwitz C, Jaureguiberry G, Rasoulpour M, Estrada E. Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasis-identification of a novel SLC34A3/NaPi-IIc mutation. Am J Med Genet A. 2011;155A(3):626–33.

    PubMed  Article  Google Scholar 

  8. Tencza AL, Ichikawa S, Dang A, Kenagy D, McCarthy E, Econs MJ, et al. Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. J Clin Endocrinol Metab. 2009;94(11):4433–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Sermet-Gaudelus I, Garabédian M, Dechaux M, Lenoir G, Rey J, Tieder M. Hereditary hypophosphatemic rickets with hypercalciuria: report of a new kindred. Nephron. 2001;88(1):83–6.

    CAS  PubMed  Article  Google Scholar 

  10. Tieder M, Modai D, Samuel R, Arie R, Halabe A, Bab I, et al. Hereditary hypophosphatemic rickets with hypercalciuria. N Engl J Med. 1985;312(10):611–7.

    CAS  PubMed  Article  Google Scholar 

  11. Tieder M, Modai D, Shared U, Samuel R, Arie R, Halabe A, et al. “Idiopathic” hypercalciuria and hereditary hypophosphatemic rickets. Two phenotypical expressions of a common genetic defect. N Engl J Med. 1987;316(3):125–9.

    CAS  PubMed  Article  Google Scholar 

  12. Tieder M, Arie R, Bab I, Maor J, Liberman UA. A new kindred with hereditary hypophosphatemic rickets with hypercalciuria: implications for correct diagnosis and treatment. Nephron. 1992;62(2):176–81.

    CAS  PubMed  Article  Google Scholar 

  13. Nishiyama S, Inoue F, Matsuda I. A single case of hypophosphatemic rickets with hypercalciuria. J Pediatr Gastroenterol Nutr. 1986;5(5):826–9.

    CAS  PubMed  Article  Google Scholar 

  14. Chen C, Carpenter T, Steg N, Baron R, Anast C. Hypercalciuric hypophosphatemic rickets, mineral balance, bone histomorphometry, and therapeutic implications of hypercalciuria. Pediatrics. 1989;84(2):276–80.

    CAS  PubMed  Google Scholar 

  15. Navarro JF, Teruel JL, Montalbán C, Gallego N, Ortuño J. Hypercalciuria secondary to chronic hypophosphatemia. Miner Electrolyte Metab. 1994;20(5):255–8.

    CAS  PubMed  Google Scholar 

  16. Santos F, Amil B, Chan JC. Síndromes hipofosfatémicos. In: García Nieto G, Santos F, editors. Nefrología pediátrica. 2nd ed. Madrid: Grupo Aula Médica; 2006. p. 161–79.

    Google Scholar 

  17. Yamamoto T, Michigami T, Aranami F, Segawa H, Yoh K, Nakajima S, et al. Hereditary hypophosphatemic rickets with hypercalciuria: a study for the phosphate transporter gene type IIc and osteoblastic function. J Bone Miner Metab. 2007;25(6):407–13.

    PubMed  Article  Google Scholar 

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

    Article  Google Scholar 

  19. Sáez-Torres C, Rodrigo D, Grases F, García-Raja AM, Gómez C, Lumbreras J, et al. Urinary excretion of calcium, magnesium, phosphate, citrate, oxalate, and uric acid by healthy schoolchildren using a 12-h collection protocol. Pediatr Nephrol. 2014;29(7):1201–8.

    PubMed  Article  Google Scholar 

  20. Jiménez R, Calderón V. Litiasis renal e hipercalciuria idiopática. Protoc Diagn Ter Pediatr. 2014;1:155–70.

    Google Scholar 

  21. Yu Y, Sanderson SR, Reyes M, Sharma A, Dunbar N, Srivastava T, et al. Novel NaPi-IIc mutations causing HHRH and idiopathic hypercalciuria in several unrelated families: long-term follow-up in one kindred. Bone. 2012;50(5):1100–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Cioffi M, Corradino M, Gazzerro P, Vietri MT, Di Macchia C, Contursi A, et al. Serum concentrations of intact parathyroid hormone in healthy children. Clin Chem. 2000;46(6 Pt 1):863–4.

    CAS  PubMed  Article  Google Scholar 

  23. Higgins V, Truong D, White-Al Habeeb NMA, Fung AWS, Hoffman B, Adeli K. Pediatric reference intervals for 1,25-dihydroxyvitamin D using the DiaSorin LIAISON XL assay in the healthy CALIPER cohort. Clin Chem Lab Med. 2018;56(6):964–72.

    CAS  PubMed  Article  Google Scholar 

  24. Mantecón L, Alonso MA, Moya V, Andrés AG, Avello N, Martínez-Morillo E, et al. Marker of vitamin D status in healthy children: free or total 25-hydroxyvitamin D? PLoS One. 2018;13(8):e0202237.

    PubMed  PubMed Central  Article  Google Scholar 

  25. Stagi S, Cavalli L, Ricci S, Mola M, Marchi C, Seminara S, et al. Parathyroid hormone levels in healthy children and adolescents. Horm Res Paediatr. 2015;84(2):124–9.

    CAS  PubMed  Article  Google Scholar 

  26. Ghazali S, Barratt TM. Urinary excretion of calcium and magnesium in children. Arch Dis Child. 1974;49(2):97–101.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Areses R, Arruebarrena D, Arriola M, Mingo T, Ugarte B, Aribieta MA. Estudio HAURTXO. Valores de referencia del citrato en plasma y orina en la edad pediátrica. Nefrología. 1994;14(3):302–7.

    Google Scholar 

  28. Pak CY. Citrate and renal calculi. Miner Electrolyte Metab. 1987;13(4):257–66.

    CAS  PubMed  Google Scholar 

  29. Hernández Marco R, Núñez Gómez F, Martínez Costa C, Fons Moreno J, Peris Vidal A, Brines SJ. Urinary excretion of calcium, magnesium, uric acid and oxalic acid in normal children. An Esp Pediatr. 1988;29(2):99–104.

    PubMed  Google Scholar 

  30. Chen YH, Lee AJ, Chen CH, Chesney RW, Stapleton FB, Roy S 3rd. Urinary mineral excretion among normal Taiwanese children. Pediatr Nephrol. 1994;8(1):36–9.

    CAS  PubMed  Article  Google Scholar 

  31. Stapleton FB, Linshaw MA, Hassanein K, Gruskin AB. Uric acid excretion in normal children. J Pediatr. 1978;92(6):911–4.

    CAS  PubMed  Article  Google Scholar 

  32. Cameron MA, Sakhaee K, Moe OW. Nephrolithiasis in children. Pediatr Nephrol. 2005;20(11):1587–92.

    PubMed  Article  Google Scholar 

  33. Metz MP. Determining urinary calcium/creatinine cut-offs for the paediatric population using published data. Ann Clin Biochem. 2006;43(Pt 5):398–401.

    CAS  PubMed  Article  Google Scholar 

  34. Matos V, van Melle G, Boulat O, Markert M, Bachmann C, Guignard JP. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr. 1997;131(2):252–7.

    CAS  PubMed  Article  Google Scholar 

  35. Areses R, Urbieta MA, Arriola M, Arruebarrena D, Garrido A, Mingo T, et al. Estudio HAURTXO. Valores de referencia del ácido úrico en sangria y orina en la infancia. Nefrología. 1994;11(4):321–6.

    Google Scholar 

  36. Hoppe B, Kemper MJ. Diagnostic examination of the child with urolithiasis or nephrocalcinosis. Pediatr Nephrol. 2010;25(3):403–13.

    PubMed  Article  Google Scholar 

  37. Leumann EP, Dietl A, Matasovic A. Urinary oxalate and glycolate excretion in healthy infants and children. Pediatr Nephrol. 1990;4(5):493–7.

    CAS  PubMed  Article  Google Scholar 

  38. Grases F, García-Ferragut L, Costa-Bauza A, Conte A, García-Raja A. Simple test to evaluate the risk of urinary calcium stone formation. Clin Chim Acta. 1997;263(1):43–55.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

This supplement has been funded by Kyowa Kirin.

Funding

Kyowa Kirin organized the scientific meeting and contributed to the financing of the publication of the opinion of the speakers presented at that meeting (Madrid, November 2018).

Medical Writing, Editorial, and Other Assistance

The author would like to thank Fernando Sánchez Barbero, PhD, and Ana María Palma Nieto on behalf of Springer Healthcare for providing medical writing assistance and translation. Kyowa Kirin funded the writing assistance provided by Springer Healthcare Ibérica S.L.

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The named author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, takes responsibility for the integrity of the work as a whole, and has given his approval for this version to be published.

Disclosures

Domingo González-Lamuño has nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.

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Correspondence to Domingo González-Lamuño.

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González-Lamuño, D. Hypophosphataemic Rickets: Diagnosis Algorithm—How Not to Make a Mistake. Adv Ther 37, 95–104 (2020). https://doi.org/10.1007/s12325-019-01184-1

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Keywords

  • Calcipenic rickets
  • Calcitriol
  • Calcium
  • FGF23
  • Phosphate
  • Phosphopenic rickets