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Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment

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Abstract

Inactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X-linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growth retardation. We assessed the efficacy of combined calcitriol and orally administered phosphate (Pi) therapy on longitudinal growth in relation to age at treatment onset in a retrospective, single-center review of children with XLHR and documented PHEX mutations. Growth was compared in those who started treatment before (G1; N = 10; six boys) and after (G2; N = 13; five boys) 1 year old. Median height standard deviation score (HSDS) at treatment onset was normal in G1: 0.1 [interquartile range (IR) −1.3 to 0.4) and significantly (p = 0.004) lower in G2 (IR −2.1 (−2.8 to −1.4). Treatment duration was similar [G1 8.5 (4.0–15.2) vs G2 11.9 (6.2–14.3) years; p = 0.56], as were prescribed phosphate and calcitriol doses. Recent HSDS was significantly (p = 0.009) better in G1 [−0.7 (−1.5 to 0.3)] vs G2 [−2.0 (−2.3 to −1.0)]. No effects of gender or genotype on growth could be identified. Children with PHEX-associated XLHR benefit from early treatment and can achieve normal growth. Minimal catchup growth was seen in those who started treatment later. Our findings emphasize the importance of early diagnosis to allow treatment before growth has been compromised.

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References

  1. 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 

  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

    Article  Google Scholar 

  3. Addison WN, Nakano Y, Loisel T, Crine P, McKee MD (2008) 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

    Article  PubMed  CAS  Google Scholar 

  4. Yan X, Yokote H, Jing X, Yao L, Sawada T, Zhang Y, Liang S, Sakaguchi K (2005) Fibroblast growth factor 23 reduces expression of type IIa Na+/Pi co-transporter by signaling through a receptor functionally distinct from the known FGFRs in opossum kidney cells. Genes Cells 10:489–502

    Article  PubMed  CAS  Google Scholar 

  5. Yuan B, Takaiwa M, Clemens TL, Feng JQ, Kumar R, Rowe PS, Xie Y, Drezner MK (2008) Aberrant PHEX function in osteoblasts and osteocytes alone underlies murine X-linked hypophosphatemia. J Clin Invest 118:722–734

    PubMed  CAS  Google Scholar 

  6. 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  PubMed  CAS  Google Scholar 

  7. Harrell RM, Lyles KW, Harrelson JM, Friedman NE, Drezner MK (1985) Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. J Clin Invest 75:1858–1868

    Article  PubMed  CAS  Google Scholar 

  8. Costa T, Marie PJ, Scriver CR, Cole DE, Reade TM, Nogrady B, Glorieux FH, Delvin EE (1981) X-linked hypophosphatemia: effect of calcitriol on renal handling of phosphate, serum phosphate, and bone mineralization. J Clin Endocrinol Metab 52:463–472

    Article  PubMed  CAS  Google Scholar 

  9. Borghi MM, Coates V, Omar HA (2005) Evaluation of stature development during childhood and adolescence in individuals with familial hypophosphatemic rickets. Scientific World Journal 5:868–873

    Article  PubMed  Google Scholar 

  10. Miyamoto J, Koto S, Hasegawa Y (2000) Final height of Japanese patients with X-linked hypophosphatemic rickets: effect of vitamin D and phosphate therapy. Endocr J 47:163–167

    Article  PubMed  CAS  Google Scholar 

  11. Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E (2003) Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 88:3591–3597

    Article  PubMed  CAS  Google Scholar 

  12. 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  PubMed  CAS  Google Scholar 

  13. Verge CF, Cowell CT, Howard NJ, Donaghue KC, Silink M (1993) Growth in children with X-linked hypophosphataemic rickets. Acta Paediatr Suppl 388:70–75, discussion 76

    PubMed  CAS  Google Scholar 

  14. Chan JC, Lovinger RD, Mamunes P (1980) Renal hypophosphatemic rickets: growth acceleration after long-term treatment with 1, 25-dihydroxyvitamin-D3. Pediatrics 66:445–454

    PubMed  CAS  Google Scholar 

  15. McEnery PT, Silverman FN, West CD (1972) Acceleration of growth with combined vitamin D-phosphate therapy of hypophosphatemic resistant rickets. J Pediatr 80:763–774

    Article  PubMed  CAS  Google Scholar 

  16. 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  PubMed  CAS  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  PubMed  CAS  Google Scholar 

  18. Rasmussen H, Pechet M, Anast C, Mazur A, Gertner J, Broadus AE (1981) Long-term treatment of familial hypophosphatemic rickets with oral phosphate and 1 alpha-hydroxyvitamin D3. J Pediatr 99:16–25

    Article  PubMed  CAS  Google Scholar 

  19. Glorieux FH, Scriver CR, Reade TM, Goldman H, Roseborough A (1972) Use of phosphate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. N Engl J Med 287:481–487

    Article  PubMed  CAS  Google Scholar 

  20. 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. Jf Clin Endocrinol Metab 93:4672–4682

    Article  CAS  Google Scholar 

  21. Stickler GB, Morgenstern BZ (1989) Hypophosphataemic rickets: final height and clinical symptoms in adults. Lancet 2:902–905

    Article  PubMed  CAS  Google Scholar 

  22. Chesney RW, Mazess RB, Rose P, Hamstra AJ, De Luca HF, Breed AL (1983) Long-term influence of calcitriol (1,25-dihydroxyvitamin D) and supplemental phosphate in X-linked hypophosphatemic rickets. Pediatrics 71:559–567

    PubMed  CAS  Google Scholar 

  23. 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  PubMed  CAS  Google Scholar 

  24. 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  PubMed  CAS  Google Scholar 

  25. Patriquin H, Robitaille P (1986) Renal calcium deposition in children: sonographic demonstration of the Anderson-Carr progression. AJR Am J Roentgenol 146:1253–1256

    PubMed  CAS  Google Scholar 

  26. 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 Clinl Endocrinol Metab 86:3889–3899

    Article  CAS  Google Scholar 

  27. Boskey A, Frank A, Fujimoto Y, Spevak L, Verdelis K, Ellis B, Troiano N, Philbrick W, Carpenter T (2009) The PHEX transgene corrects mineralization defects in 9 month-old hypophosphatemic mice. Calcif Tissue Int 84:126–137

    Article  PubMed  CAS  Google Scholar 

  28. Qiu ZQ, Travers R, Rauch F, Glorieux FH, Scriver CR, Tenenhouse HS (2004) Effect of gene dose and parental origin on bone histomorphometry in X-linked hyp mice. Bone 34:134–139

    Article  PubMed  CAS  Google Scholar 

  29. 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  PubMed  CAS  Google Scholar 

  30. 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

    PubMed  CAS  Google Scholar 

  31. 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  PubMed  CAS  Google Scholar 

  32. Schonaue E, Kruse K, Bohles HJ, Sewell AC (1992) More evidence for hyperoxaluria in phosphate-treated X-linked familial hypophosphataemic rickets. Eur J Pediatr 151:390

    Article  PubMed  CAS  Google Scholar 

  33. Alon U, Donaldson DL, Hellerstein S, Warady BA, Harris DJ (1992) Metabolic and histologic investigation of the nature of nephrocalcinosis in children with hypophosphatemic rickets and in the hyp mouse. J Pediatr 120:899–905

    Article  PubMed  CAS  Google Scholar 

  34. Goodyer PR, Kronick JB, Jequier S, Reade TM, Scriver CR (1987) Nephrocalcinosis and its relationship to treatment of hereditary rickets. J Pediatr 111:700–704

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Nephro-Urology, Great Ormond Street Hospital, London, UK

    Catherine Quinlan, Detlef Bockenhauer, William Van’t Hoff & Aoife M. Waters

  2. Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK

    Katie Guegan & Sian Ellard

  3. Sheffield Children’s NHS Foundation Trust, Western Bank Sheffield, Sheffield, UK

    Amaka Offiah

  4. Vascular Radiology, Nottingham University NHS Trust, Nottingham, UK

    Richard O’ Neill & Melanie P. Hiorns

  5. Department of Nephro-Urology, Great Ormond Street Children’s Hospital, London, WC1N 3JH, UK

    Aoife M. Waters

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  1. Catherine Quinlan
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  2. Katie Guegan
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Correspondence to Aoife M. Waters.

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Quinlan, C., Guegan, K., Offiah, A. et al. Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol 27, 581–588 (2012). https://doi.org/10.1007/s00467-011-2046-z

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  • DOI: https://doi.org/10.1007/s00467-011-2046-z

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