Skip to main content
SpringerLink
Log in

Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Children with X-linked hypophosphatemic rickets (XLH) are prone to severe stunting. A multicenter mixed-longitudinal study was conducted to assess age-related stature, sitting height, arm and leg length in XLH patients on continuous treatment with phosphate and calcitriol. Mean standard deviation scores (SDS) for all body dimensions were markedly reduced and differed significantly among each other at the initial and subsequent evaluations (baseline: stature −2.48 SDS; sitting height −0.99 SDS; arm length −1.81 SDS; leg length −2.90 SDS; each p < 0.001). A strong association between stature and leg length (r 2= 0.87, p < 0.001) was noted. Leg length SDS decreased progressively during childhood (2–9 years) and adolescence (12–15 years; each p < 0.001). Sitting height SDS increased significantly during late childhood, indicating uncoupled growth of the legs and trunk and resulting in an ever increasing sitting height index (i.e. ratio of sitting height to stature; age 2 years 2.0 SDS; age 10 years 3.3 SDS; p < 0.001) that was associated with the degree of stunting (r 2 = 0.314, p< 0.001). Mean serum phosphate levels were positively associated with stature and leg length, but negatively with sitting height index. Based on these results, we can conclude that growth of the legs and trunk is uncoupled in XLH and related to serum phosphate levels.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

FGF-23:

fibroblast growth factor-23

PHEX:

phosphate regulating endopeptidase homolog X-linked

PTH:

parathyroid hormone

rhGH:

recombinant human growth hormone

SDS:

standard deviation score

XLH:

X-linked hypophosphatemic rickets

References

  1. Bastepe M, Jüppner H (2008) Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation. Rev Endocr Metab Disord 9:171–180

    Article  PubMed  Google Scholar 

  2. The HYP Consortium (1995) A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 11:130–136

    Google Scholar 

  3. Ichikawa S, Traxler EA, Estwick SA, Curry LR, Johnson ML, Sorenson AH, Imel EA, Econs MJ (2008) Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets. Bone 43:663–666

    Article  CAS  PubMed  Google Scholar 

  4. Jan de Beur SM, Levine MA (2002) Molecular pathogenesis of hypophosphatemic rickets. J Clin Endocrinol Metab 87:2467–2473

    Article  PubMed  Google Scholar 

  5. Strom TM, Jüppner H (2008) PHEX, FGF23, DMP1 and beyond. Curr Opin Nephrol Hypertens 17:357–362

    Article  CAS  PubMed  Google Scholar 

  6. Alon US (2006) Hypophosphatemic vitamin-D resistant rickets. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. American Society of Bone and Mineral Research, Washington D.C., pp 342–345

  7. Reusz GS, Latta K, Hoyer PF, Byrd DJ, Ehrich JH, Brodehl J (1990) Evidence suggesting hyperoxaluria as a cause of nephrocalcinosis in phosphate-treated hypophosphataemic rickets. Lancet 335:1240–1243

    Article  CAS  PubMed  Google Scholar 

  8. Patzer L, van't Hoff W, Shah V, Hallson P, Kasidas GP, Samuell C, de Bruyn R, Barratt TM, Dillon MJ (1999) Urinary supersaturation of calcium oxalate and phosphate in patients with X-linked hypophosphatemic rickets and in healthy schoolchildren. J Pediatr 135:611–617

    Article  CAS  PubMed  Google Scholar 

  9. Kooh SW, Binet A, Daneman A (1994) Nephrocalcinosis in X-linked hypophosphataemic rickets: its relationship to treatment, kidney function, and growth. Clin Invest Med 17:123–130

    CAS  PubMed  Google Scholar 

  10. Schmitt CP, Mehls O (2004) The enigma of hyperparathyroidism in hypophosphatemic rickets. Pediatr Nephrol 19:473–477

    Article  PubMed  Google Scholar 

  11. Berndt M, Ehrich JH, Lazovic D, Zimmermann J, Hillmann G, Kayser C, Prokop M, Schirg E, Siegert B, Wolff G, Brodehl J (1996) Clinical course of hypophosphatemic rickets in 23 adults. Clin Nephrol 45:33–41

    CAS  PubMed  Google Scholar 

  12. Friedman NE, Lobaugh B, Drezner MK (1993) Effects of calcitriol and phosphorus therapy on the growth of patients with X-linked hypophosphatemia. J Clin Endocrinol Metab 76:839–844

    Article  CAS  PubMed  Google Scholar 

  13. Glorieux FH, Marie PJ, Pettifor JM, Delvin EE (1980) Bone response to phosphate salts, ergocalciferol, and calcitriol in hypophosphatemic vitamin D-resistant rickets. N Engl J Med 303:1023–1031

    Article  CAS  PubMed  Google Scholar 

  14. Haffner D, Weinfurth A, Manz F, Schmidt H, Bremer HJ, Mehls O, Scharer K (1999) Long-term outcome of paediatric patients with hereditary tubular disorders. Nephron 83:250–260

    Article  CAS  PubMed  Google Scholar 

  15. Haffner D, Nissel R, Wuhl E, Mehls O (2004) Effects of growth hormone treatment on body proportions and final height among small children with X-linked hypophosphatemic rickets. Pediatrics 113:e593–e596

    Article  PubMed  Google Scholar 

  16. Steendijk R, Hauspie RC (1992) The pattern of growth and growth retardation of patients with hypophosphataemic vitamin D-resistant rickets: a longitudinal study. Eur J Pediatr 151:422–427

    Article  CAS  PubMed  Google Scholar 

  17. Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M (1991) Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med 325:1843–1848

    Article  CAS  PubMed  Google Scholar 

  18. Steendijk R, Herweijer TJ (1984) Height, sitting height and leg length in patients with hypophosphataemic rickets. Acta Paediatr Scand 73:181–184

    Article  CAS  PubMed  Google Scholar 

  19. Ariceta G, Langman CB (2007) Growth in X-linked hypophosphatemic rickets. Eur J Pediatr 166:303–309

    Article  CAS  PubMed  Google Scholar 

  20. Petersen DJ, Boniface AM, Schranck FW, Rupich RC, Whyte MP (1992) X-linked hypophosphatemic rickets: a study (with literature review) of linear growth response to calcitriol and phosphate therapy. J Bone Miner Res 7:583–597

    Article  CAS  PubMed  Google Scholar 

  21. Reusz GS, Hoyer PF, Lucas M, Krohn HP, Ehrich JH, Brodehl J (1990) X linked hypophosphataemia: treatment, height gain, and nephrocalcinosis. Arch Dis Child 65:1125–1128

    Article  CAS  PubMed  Google Scholar 

  22. Seikaly MG, Waber PG, Baum M (2008) Urinary prostaglandins and the effect of indomethacin on phosphate excretion in children with hypophosphatemic rickets. Pediatr Res 64:210–212

    Article  CAS  PubMed  Google Scholar 

  23. Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y (2005) A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res 58:329–333

    Article  CAS  PubMed  Google Scholar 

  24. Hoyer PF (1996) Nephrokalzinose. In: Hofmann V, Deeg KH, Hoyer PF (eds) Ultraschall-diagnostik in Pädiatrie und Kinderchirurgie. Thieme, Stuttgart, New York, pp 372–374

    Google Scholar 

  25. Weiner JS, Lourie JA (1981) Practical human biology. Academic Press, London

    Google Scholar 

  26. Živičnjak M, Franke D, Filler G, Haffner D, Froede K, Nissel R, Haase S, Offner G, Ehrich JH, Querfeld U (2007) Growth impairment shows an age-dependent pattern in boys with chronic kidney disease. Pediatr Nephrol 22:420–429

    Article  PubMed  Google Scholar 

  27. Živičnjak M, Narancic NS, Szirovicza L, Franke D, Hrenovic J, Bisof V (2003) Gender-specific growth patterns for stature, sitting height and limbs length in Croatian children and youth (3 to 18 years of age). Coll Antropol 27:321–334

    PubMed  Google Scholar 

  28. Zivicnjak M, Smolej Narancic N, Szirovicza L, Franke D, Hrenovic J, Bisof V, Tomas Z, Skaric-Juric T (2008) Gender-specific growth patterns of transversal body dimensions in Croatian children and youth (2 to 18 years of age). Coll Antropol 32:419–431

    PubMed  Google Scholar 

  29. Kruse K, Hinkel GK, Griefahn B (1998) Calcium metabolism and growth during early treatment of children with X-linked hypophosphataemic rickets. Eur J Pediatr 157:894–900

    Article  CAS  PubMed  Google Scholar 

  30. Pedersen HE, Mc CH (1951) Vitamin-resistant rickets. J Bone Joint Surg Am 33:203–220

    CAS  PubMed  Google Scholar 

  31. Imel EA, DiMeglio LA, Hui SL, Carpenter TO, Econs MJ (2010) Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab 95:1846–1850

    Article  CAS  PubMed  Google Scholar 

  32. Wesseling-Perry K, Pereira RC, Wang H, Elashoff RM, Sahney S, Gales B, Juppner H, Salusky IB (2009) Relationship between plasma fibroblast growth factor-23 concentration and bone mineralization in children with renal failure on peritoneal dialysis. J Clin Endocrinol Metab 94:511–517

    Article  CAS  PubMed  Google Scholar 

  33. Rauch F (2009) Overview of rickets in children. UpToDate, Inc. Available at: http://www.uptodate.com

  34. Gaucher C, Walrant-Debray O, Nguyen TM, Esterle L, Garabedian M, Jehan F (2009) PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet 125:401–411

    Article  PubMed  Google Scholar 

  35. Ruchon AF, Tenenhouse HS, Marcinkiewicz M, Siegfried G, Aubin JE, DesGroseillers L, Crine P, Boileau G (2000) Developmental expression and tissue distribution of Phex protein: effect of the Hyp mutation and relationship to bone markers. J Bone Miner Res 15:1440–1450

    Article  CAS  PubMed  Google Scholar 

  36. Ecarot B, Glorieux FH, Desbarats M, Travers R, Labelle L (1995) Effect of 1, 25-dihydroxyvitamin D3 treatment on bone formation by transplanted cells from normal and X-linked hypophosphatemic mice. J Bone Miner Res 10:424–431

    Article  CAS  PubMed  Google Scholar 

  37. Holm IA, Nelson AE, Robinson BG, Mason RS, Marsh DJ, Cowell CT, Carpenter TO (2001) Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 86:3889–3899

    Article  CAS  PubMed  Google Scholar 

  38. Jehan F, Gaucher C, Nguyen TM, Walrant-Debray O, Lahlou N, Sinding C, Dechaux M, Garabedian M (2008) Vitamin D receptor genotype in hypophosphatemic rickets as a predictor of growth and response to treatment. J Clin Endocrinol Metab 93:4672–4682

    Article  CAS  PubMed  Google Scholar 

  39. Baroncelli GI, Bertelloni S, Ceccarelli C, Saggese G (2001) Effect of growth hormone treatment on final height, phosphate metabolism, and bone mineral density in children with X-linked hypophosphatemic rickets. J Pediatr 138:236–243

    Article  CAS  PubMed  Google Scholar 

  40. Haffner D, Wuhl E, Blum WF, Schaefer F, Mehls O (1995) Disproportionate growth following long-term growth hormone treatment in short children with X-linked hypophosphataemia. Eur J Pediatr 154:610–613

    Article  CAS  PubMed  Google Scholar 

  41. Seikaly MG, Brown R, Baum M (1997) The effect of recombinant human growth hormone in children with X-linked hypophosphatemia. Pediatrics 100:879–884

    Article  CAS  PubMed  Google Scholar 

  42. Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD (2008) Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol 3:658–664

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank all the members of the Hypophosphatemic Rickets Study Group of the "Arbeitsgemeinschaft für Pädiatrische Endokrinologie" and the “Gesellschaft für Pädiatrische Nephrologie" for their help in the design and realization of this project. We very much appreciate the willingness of our patients and their families to participate in this trial.

Funding sources

This project was supported by Pfizer, Berlin, Germany.

Conflict of interest statement

D. Schnabel and D. Haffner are consultants of Pfizer.

Author information

Authors and Affiliations

  1. Department of Pediatric Nephrology, Children’s Hospital of Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Miroslav Živičnjak

  2. Department of Pediatrics, University Children’s Hospital, Charité, 13353, Berlin, Germany

    Dirk Schnabel, Heiko Billing & Uwe Querfeld

  3. Department of Pediatrics, University of Rostock, 18057, Rostock, Germany

    Hagen Staude & Dieter Haffner

  4. Department of Pediatrics, Children’s Hospital, London Health Science Centre, University of Western Ontario, N6A 5W9, London, ON, Canada

    Guido Filler

  5. Department of Pediatrics, University of Lübeck, 23538, Lübeck, Germany

    Marius Schumacher

  6. Department of Pediatrics, University of Dresden, 01307, Dresden, Germany

    Anke Pyper

  7. Department of Pediatrics, University of Greifswald, 17475, Greifswald, Germany

    Carmen Schröder

  8. Department of Pediatrics, University of Münster, 48149, Münster, Germany

    Jürgen Brämswig

Authors
  1. Miroslav Živičnjak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dirk Schnabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heiko Billing
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hagen Staude
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guido Filler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Uwe Querfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marius Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anke Pyper
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Carmen Schröder
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jürgen Brämswig
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Dieter Haffner
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Hypophosphatemic Rickets Study Group of the “Arbeitsgemeinschaft für Pädiatrische Endokrinologie” and “Gesellschaft für Pädiatrische Nephrologie”

Corresponding author

Correspondence to Miroslav Živičnjak.

Additional information

List of contributing investigators

Austria: K. Kapelari (Innsbruck); Germany: D. Schnabel, H. Billing, U. Querfeld, J. Gellermann (Berlin), N. Jorch (Bielefeld), G. Simic-Schleicher (Bremen), G. Even, E. Schönau (Cologne), C. Plank, D. Simm (Erlangen), K.E. Bonzel, R. Büscher (Essen), C. Jacobi, M. Pohl (Freiburg), D. Wölfel (Göppingen), C. Schröder (Greifswald), M. Živičnjak, D. Franke, J.H. Ehrich (Hannover), E. Wühl, B. Tönshoff (Heidelberg), E. Schmid (Hirschaid), J. Kühr, U. Blaich (Karlsruhe), O. Hiort, M. Schumacher (Lübeck), H.-P. Weber (Lüdenscheid), K. Mohnike (Magdeburg), R. Beetz (Mainz), G. Rabl (Munich), J.H. Brämswig (Münster), M. Wigger, H. Staude, D. Haffner (Rostock), M. Holder (Stuttgart), St. Kant, W. Rauh (Trier)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Živičnjak, M., Schnabel, D., Billing, H. et al. Age-related stature and linear body segments in children with X-linked hypophosphatemic rickets. Pediatr Nephrol 26, 223–231 (2011). https://doi.org/10.1007/s00467-010-1705-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-010-1705-9

Keywords

Search

Navigation