Skip to main content
SpringerLink
Log in

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

  • Review
  • Published:
Advances in Therapy Aims and scope Submit manuscript

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.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

    Article  CAS  PubMed  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.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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.

    Article  PubMed  PubMed Central  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.

    Article  CAS  PubMed  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.

    Article  PubMed  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.

    Article  CAS  PubMed  PubMed Central  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  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.

    Article  PubMed  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.

    Article  PubMed  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.

    Article  CAS  PubMed  PubMed Central  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  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.

    Article  PubMed  PubMed Central  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  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.

    Article  PubMed  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.

    Article  CAS  PubMed  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.

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Authorship

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.

Author information

Authors and Affiliations

  1. Profesor Titular de Pediatría, Universidad de Cantabria, Servicio de Pediatría, Hospital Universitario Marqués de Valdecilla, Santander, Spain

    Domingo González-Lamuño

Authors
  1. Domingo González-Lamuño
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Domingo González-Lamuño.

Additional information

Enhanced Digital Features

To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.10329947.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

González-Lamuño, D. Hypophosphataemic Rickets: Diagnosis Algorithm—How Not to Make a Mistake. Adv Ther 37 (Suppl 2), 95–104 (2020). https://doi.org/10.1007/s12325-019-01184-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-019-01184-1

Keywords

Search

Navigation