Diagnostic and New Therapeutic Approaches to Two Challenging Pediatric Metabolic Bone Disorders: Hypophosphatasia and X-linked Hypophosphatemic Rickets


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The diagnosis and management of metabolic bone disease among children can be challenging. This difficulty could be due to many factors, including limited awareness of these rare conditions, the complex pathophysiology of calcium and phosphate homeostasis, the overlapping phenotype with more common disorders (such as rickets), and the lack of specific treatments for these rare disorders. As a result, affected individuals could experience delayed diagnosis or misdiagnosis, leading to improper management. In this review, we describe the challenges facing diagnostic and therapeutic approaches to two metabolic bone disorders (MBD) among children: hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH). We focus on explaining the pathophysiological processes that conceptually underpin novel therapeutic approaches, as well as these conditions’ clinical or radiological similarity to nutritional rickets. Particularly in areas with limited sun exposure and among patients not supplementing vitamin D, nutritional rickets are still more common than HPP and XLH, and pediatricians and primary physicians frequently encounter this disorder in their practices. More recently, our understanding of these disorders has significantly improved, leading to the development of novel therapies. Asfotas alfa, a recombinant, human- tissue, nonspecific alkaline phosphatase, improved the survival of patients with HPP. Burosumab, a human monoclonal anti-FGF23 antibody, was recently approved as a specific therapy for XLH. We also highlight the current evidence on these two specific therapies’ safety and effectiveness, though long-term data are still needed. Both HPP and XLH are multisystemic disorders that should be managed by multidisciplinary teams. Finally, recognizing these conditions in early stages will enable affected children and young adults to benefit from newly introduced, specific therapies.

作者简介

Fahad Aljuraibah

Department of Pediatrics, King Abdullah Specialist Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs

编辑信件的主要联系方式.
Email: info@benthamscience.net

Ibrahim Alalwan

Department of Pediatrics, King Abdullah Specialist Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs,

Email: info@benthamscience.net

Abdelhadi Habeb

Department of Pediatrics, Prince Mohammed bin Abdulaziz Hospital for National Guard

Email: info@benthamscience.net

参考

  1. Michigami T. Skeletal mineralization: Mechanisms and diseases. Ann Pediatr Endocrinol Metab 2019; 24(4): 213-9. doi: 10.6065/apem.2019.24.4.213 PMID: 31905439
  2. Ukarapong S, Seeherunvong T, Berkovitz G. Current and emerging therapies for pediatric bone diseases. Clin Rev Bone Miner Metab 2020; 18(1-3): 31-42. doi: 10.1007/s12018-020-09272-5
  3. Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol 2008 Nov;3; (Suppl 3): S131-9. PMID: 18988698; PMCID: PMC3152283. doi: 10.2215/CJN.04151206
  4. Bonjour JP. Calcium and phosphate: A duet of ions playing for bone health. J Am Coll Nutr 2011; 30(5) (Suppl. 1): 438S-48S. doi: 10.1080/07315724.2011.10719988 PMID: 22081690
  5. Hasegawa T, Yamamoto T, Tsuchiya E, et al. Ultrastructural and biochemical aspects of matrix vesicle-mediated mineralization. Jpn Dent Sci Rev 2017; 53(2): 34-45. doi: 10.1016/j.jdsr.2016.09.002 PMID: 28479934
  6. Sun M, Wu X, Yu Y, et al. Disorders of calcium and phosphorus metabolism and the proteomics/metabolomics-based research. Front Cell Dev Biol 2020; 8: 576110. doi: 10.3389/fcell.2020.576110 PMID: 33015068
  7. Meah F, Basit A, Emanuele N, Emanuele MA. Hypophosphatasia: Review of bone mineral metabolism, pathophysiology, clinical presentation, diagnosis, and treatment. Clin Rev Bone Miner Metab 2017; 15(1): 24-36. doi: 10.1007/s12018-016-9225-1
  8. Rathbun JC. Hypophosphatasia; A new developmental anomaly. AMA Am J Dis Child 1948; 75(6): 822-31. doi: 10.1001/archpedi.1948.02030020840003 PMID: 18110134
  9. Sobel EH, Clark LC Jr, Fox RP, Robinow M. Rickets, deficiency of alkaline phosphatase activity and premature loss of teeth in childhood. Pediatrics 1953; 11(4): 309-22. doi: 10.1542/peds.11.4.309 PMID: 13055342
  10. Mccance RA, Morrison AB, Dent CE. The excretion of phosphoethanolamine and hypophosphatasia. Lancet 1955; 265(6855): 131. doi: 10.1016/S0140-6736(55)91704-9 PMID: 13222868
  11. Hypophosphatasia FD. Am J Med 1957; 22(5): 730-46. doi: 10.1016/0002-9343(57)90124-9 PMID: 13410963
  12. Russell R. Excretion of inorganic pyrophosphate in hypophosphatasia. Lancet 1965; 286(7410): 461-4. doi: 10.1016/S0140-6736(65)91422-4 PMID: 14337825
  13. Whyte MP, Mahuren JD, Vrabel LA, Coburn SP. Markedly increased circulating pyridoxal-5′-phosphate levels in hypophosphatasia. Alkaline phosphatase acts in vitamin B6 metabolism. J Clin Invest 1985; 76(2): 752-6. doi: 10.1172/JCI112031 PMID: 4031070
  14. Greenberg CR, Taylor CLD, Haworth JC, et al. A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites. Genomics 1993; 17(1): 215-7. doi: 10.1006/geno.1993.1305 PMID: 8406453
  15. Sharma U, Pal D, Prasad R. Alkaline phosphatase: An overview. Indian J Clin Biochem 2014; 29(3): 269-78. doi: 10.1007/s12291-013-0408-y PMID: 24966474
  16. Hofmann C, Girschick HJ, Mentrup B, et al. Clinical aspects of hypophosphatasia: An update. Clin Rev Bone Miner Metab 2013; 11(2): 60-70. doi: 10.1007/s12018-013-9139-0
  17. Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H. Structure of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem 1988; 263(24): 12002-10. doi: 10.1016/S0021-9258(18)37885-2 PMID: 3165380
  18. Whyte MP. Hypophosphatasia — aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol 2016; 12(4): 233-46. doi: 10.1038/nrendo.2016.14 PMID: 26893260
  19. Mornet E, Taillandier A, Domingues C, et al. Hypophosphatasia: A genetic-based nosology and new insights in genotype-phenotype correlation. Eur J Hum Genet 2021; 29(2): 289-99. doi: 10.1038/s41431-020-00732-6 PMID: 32973344
  20. Mornet E, Yvard A, Taillandier A, Fauvert D, Simon-Bouy B. A molecular-based estimation of the prevalence of hypophosphatasia in the European population. Ann Hum Genet 2011; 75(3): 439-45. doi: 10.1111/j.1469-1809.2011.00642.x PMID: 21488855
  21. Tsang T, Raghuwanshi MP. Hypophosphatasia misdiagnosed as osteoporosis in a young girl. J Endocr Soc 2021; 5 (Suppl. 1): A201-2. doi: 10.1210/jendso/bvab048.409
  22. Högler W, Langman C, Gomes da Silva H, et al. Diagnostic delay is common among patients with hypophosphatasia: Initial findings from a longitudinal, prospective, global registry. BMC Musculoskelet Disord 2019; 20(1): 80. doi: 10.1186/s12891-019-2420-8 PMID: 30764793
  23. Estey MP, Cohen AH, Colantonio DA, et al. CLSI-based transference of the caliper database of pediatric reference intervals from abbott to beckman, ortho, roche and siemens clinical chemistry assays: direct validation using reference samples from the CALIPER cohort. Clin Biochem 2013; 46(13-14): 1197-219. doi: 10.1016/j.clinbiochem.2013.04.001 PMID: 23578738
  24. Fontes R, Cavalari E, Vieira Neto L, et al. Alkaline phosphatase: Reference interval transference from CALIPER to a pediatric Brazilian population. J Bras Patol Med Lab 2018; 54(4): 227-31. doi: 10.5935/1676-2444.20180039
  25. clinic Mayo. Alkaline phosphatase, serum 2022. available at: https://www.mayocliniclabs.com/test-catalog/overview/8340#Clinical-and-Interpretive
  26. Michigami T, Ohata Y, Fujiwara M, et al. Clinical practice guidelines for hypophosphatasia. Clin Pediatr Endocrinol 2020; 29(1): 9-24. doi: 10.1297/cpe.29.9 PMID: 32029969
  27. Offiah AC, Vockley J, Munns CF, Murotsuki J. Differential diagnosis of perinatal hypophosphatasia: Radiologic perspectives. Pediatr Radiol 2019; 49(1): 3-22. doi: 10.1007/s00247-018-4239-0 PMID: 30284005
  28. Unger S, Mornet E, Mundlos S, Blaser S, Cole D. Severe cleidocranial dysplasia can mimic hypophosphatasia. Eur J Pediatr 2002; 161(11): 623-6. doi: 10.1007/s00431-002-0978-9 PMID: 12424591
  29. McKiernan FE, Shrestha LK, Berg RL, Fuehrer J. Acute hypophosphatasemia. Osteoporos Int 2014; 25(2): 519-23. doi: 10.1007/s00198-013-2447-x PMID: 23912555
  30. Rodriguez E, Bober MB, Davey L, et al. Respiratory mechanics in an infant with perinatal lethal hypophosphatasia treated with human recombinant enzyme replacement therapy. Pediatr Pulmonol 2012; 47(9): 917-22. doi: 10.1002/ppul.22527 PMID: 22328548
  31. Plecko B, Stöckler S. Vitamin B6 dependent seizures. Can J Neurol Sci 2009; 36 (Suppl. 2): S73-7. PMID: 19760909
  32. Kishnani PS, Rush ET, Arundel P, et al. Monitoring guidance for patients with hypophosphatasia treated with asfotase alfa. Mol Genet Metab 2017; 122(1-2): 4-17. doi: 10.1016/j.ymgme.2017.07.010 PMID: 28888853
  33. Vogt M, Girschick H, Schweitzer T, et al. Pediatric hypophosphatasia: Lessons learned from a retrospective single-center chart review of 50 children. Orphanet J Rare Dis 2020; 15(1): 212. doi: 10.1186/s13023-020-01500-x PMID: 32811521
  34. Rassie K, Dray M, Michigami T, Cundy T. Bisphosphonate use and fractures in adults with hypophosphatasia. JBMR Plus 2019; 3(10): e10223. doi: 10.1002/jbm4.10223 PMID: 31687651
  35. Whyte MP, Mumm S, Deal C. Adult hypophosphatasia treated with teriparatide. J Clin Endocrinol Metab 2007; 92(4): 1203-8. doi: 10.1210/jc.2006-1902 PMID: 17213282
  36. Whyte MP, Valdes R Jr, Ryan LM, McAlister WH. Infantile hypophosphatasia: Enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with paget bone disease. J Pediatr 1982; 101(3): 379-86. doi: 10.1016/S0022-3476(82)80061-9 PMID: 7108657
  37. Cahill RA, Wenkert D, Perlman SA, et al. Infantile hypophosphatasia: Transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab 2007; 92(8): 2923-30. doi: 10.1210/jc.2006-2131 PMID: 17519318
  38. Scott LJ. Asfotase alfa in perinatal/infantile-onset and juvenile-onset hypophosphatasia: A guide to its use in the Usa. BioDrugs 2016; 30(1): 41-8. doi: 10.1007/s40259-016-0161-x PMID: 26832358
  39. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med 2012; 366(10): 904-13. doi: 10.1056/NEJMoa1106173 PMID: 22397652
  40. Whyte MP, Simmons JH, Moseley S, et al. Asfotase alfa for infants and young children with hypophosphatasia: 7 year outcomes of a single-arm, open-label, phase 2 extension trial. Lancet Diabetes Endocrinol 2019; 7(2): 93-105. doi: 10.1016/S2213-8587(18)30307-3 PMID: 30558909
  41. Whyte MP, Rockman-Greenberg C, Ozono K, et al. Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia. J Clin Endocrinol Metab 2016; 101(1): 334-42. doi: 10.1210/jc.2015-3462 PMID: 26529632
  42. Hofmann CE, Harmatz P, Vockley J, et al. Efficacy and safety of asfotase alfa in infants and young children with hypophosphatasia: A phase 2 open-label study. J Clin Endocrinol Metab 2019; 104(7): 2735-47. doi: 10.1210/jc.2018-02335 PMID: 30811537
  43. Whyte MP, Madson KL, Phillips D, et al. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight 2016; 1(9): e85971. doi: 10.1172/jci.insight.85971 PMID: 27699270
  44. Kishnani PS, Rockman-Greenberg C, Rauch F, et al. Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia. Bone 2019; 121: 149-62. doi: 10.1016/j.bone.2018.12.011 PMID: 30576866
  45. Reis FS, Gomes DC, Arantes HP, Lazaretti-Castro M. A two-year follow-up of asfotase alfa replacement in a patient with hypophosphatasia: Clinical, biochemical, and radiological evaluation. Arch Endocrinol Metab 2021; 64(5): 623-9. PMID: 34033304
  46. Beck-Nielsen SS, Mughal Z, Haffner D, et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J Rare Dis 2019; 14(1): 58. doi: 10.1186/s13023-019-1014-8 PMID: 30808384
  47. Lambert AS, Zhukouskaya V, Rothenbuhler A, Linglart A. X-linked hypophosphatemia: Management and treatment prospects. Joint Bone Spine 2019; 86(6): 731-8. doi: 10.1016/j.jbspin.2019.01.012 PMID: 30711691
  48. Michigami T, Ozono K. Roles of phosphate in skeleton. Front Endocrinol 2019; 10: 180. doi: 10.3389/fendo.2019.00180 PMID: 30972027
  49. Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA, Pettifor JM. Rickets. Nat Rev Dis Primers 2017; 3(1): 17101. doi: 10.1038/nrdp.2017.101 PMID: 29265106
  50. Aljuraibah F, Bacchetta J, Brandi ML, et al. An expert perspective on phosphate dysregulation with a focus on chronic hypophosphatemia. J Bone Miner Res 2022; 37(1): 12-20. doi: 10.1002/jbmr.4486 PMID: 34870347
  51. Park PG, Lim SH, Lee H, Ahn YH, Cheong HI, Kang HG. Genotype and phenotype analysis in x-linked hypophosphatemia. Front Pediatr 2021; 9: 699767. doi: 10.3389/fped.2021.699767 PMID: 34434907
  52. Chesher D, Oddy M, Darbar U, et al. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. J Inherit Metab Dis 2018; 41(5): 865-76. doi: 10.1007/s10545-018-0147-6 PMID: 29460029
  53. Padidela R, Nilsson O, Makitie O, et al. The international X-linked hypophosphataemia (XLH) registry (NCT03193476): Rationale for and description of an international, observational study. Orphanet J Rare Dis 2020; 15(1): 172. doi: 10.1186/s13023-020-01434-4 PMID: 32605590
  54. Braekeleer MD, Larochelle J. Population genetics of vitamin D-dependent rickets in northeastern Quebec. Ann Hum Genet 1991; 55(4): 283-90. doi: 10.1111/j.1469-1809.1991.tb00855.x PMID: 1687883
  55. Al Jurayyan NA, Mohamed S, Al Issa SD, Al Jurayyan AN. Rickets and osteomalacia in Saudi children and adolescents attending endocrine clinic, Riyadh, Saudi Arabia. Sudan J Paediatr 2012; 12(1): 56-63. PMID: 27493329
  56. Prentice A. Nutritional rickets around the world. J Steroid Biochem Mol Biol 2013; 136: 201-6. doi: 10.1016/j.jsbmb.2012.11.018 PMID: 23220549
  57. Alenazi B, Molla MAM, Alshaya A, Saleh M. X-linked hypophosphatemic rickets (PHEX mutation): A case report and literature review. Sudan J Paediatr 2017; 17(1): 61-5. PMID: 29213174
  58. Peter PR, Brownstein CA, Yao GQ, et al. An unusual case of rickets and how whole exome sequencing helped to correct a diagnosis. AACE Clin Case Rep 2016; 2(4): ee278-83. doi: 10.4158/EP15944.CR
  59. Babiker AMI, Al Gadi I, Al-Jurayyan NAM, et al. A novel pathogenic mutation of the CYP27B1 gene in a patient with vitamin D-dependent rickets type 1: A case report. BMC Res Notes 2014; 7(1): 783. doi: 10.1186/1756-0500-7-783 PMID: 25371233
  60. Ridefelt P, Hilsted L, Juul A, Hellberg D, Rustad P. Pediatric reference intervals for general clinical chemistry components – merging of studies from Denmark and Sweden. Scand J Clin Lab Invest 2018; 78(5): 365-72. doi: 10.1080/00365513.2018.1474493 PMID: 29806781
  61. Koljonen L, Enlund-Cerullo M, Hauta-alus H, et al. Phosphate concentrations and modifying factors in healthy children from 12 to 24 months of age. J Clin Endocrinol Metab 2021; 106(10): 2865-75. doi: 10.1210/clinem/dgab495 PMID: 34214153
  62. Deeb A, Juraibah FA, Dubayee MA, Habeb A. X-linked Hypophosphatemic Rickets: Awareness, knowledge, and practice of pediatric endocrinologists in Arab Countries. J Pediatr Genet 2020; 11(2): 126-31. PMID: 35769954
  63. Clinic Mayo. Phosphorus (inorganic), serum 2021. Available at: https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/8408
  64. Coriell MB, Van Hersh AT, Shah S. Prolonged seizure activity followed by severe hyperphosphatemia and hypocalcemia in a pediatric patient. Cureus 2021; 13(4): e14338. doi: 10.7759/cureus.14338 PMID: 33968541
  65. Al Juraibah F, Al Amiri E, Al Dubayee M, et al. Diagnosis and management of x-linked hypophosphatemia in children and adolescent in the gulf cooperation council countries. Arch Osteoporos 2021; 16(1): 52. doi: 10.1007/s11657-021-00879-9 PMID: 33660084
  66. Balasubramaniyan M, Kaur A, Sinha A, Gopinathan NR. Metaphyseal dysplasia, Spahr type: A mimicker of rickets. BMJ Case Rep 2019; 12(8): e230257. doi: 10.1136/bcr-2019-230257 PMID: 31413057
  67. Al Kaissi A, Ghachem MB, Nabil NM, et al. Schmid’s type of metaphyseal chondrodysplasia: Diagnosis and management. Orthop Surg 2018; 10(3): 241-6. doi: 10.1111/os.12382 PMID: 30027601
  68. Haffner D, Emma F, Eastwood DM, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019; 15(7): 435-55. doi: 10.1038/s41581-019-0152-5 PMID: 31068690
  69. Thiele S, Werner R, Stubbe A, Hiort O, Hoeppner W. Validation of a next-generation sequencing (NGS) panel to improve the diagnosis of X-linked hypophosphataemia (XLH) and other genetic disorders of renal phosphate wasting. Eur J Endocrinol 2020; 183(5): 497-504. doi: 10.1530/EJE-20-0275 PMID: 33107440
  70. Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect 2014; 3(1): R13-30. doi: 10.1530/EC-13-0103 PMID: 24550322
  71. Lyseng-Williamson KA. Burosumab in X-linked hypophosphatemia: A profile of its use in the USA. Drugs Ther Perspect 2018; 34(11): 497-506. doi: 10.1007/s40267-018-0560-9 PMID: 30459508
  72. Whyte MP, Carpenter TO, Gottesman GS, et al. Efficacy and safety of burosumab in children aged 1–4 years with X-linked hypophosphataemia: A multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol 2019; 7(3): 189-99. doi: 10.1016/S2213-8587(18)30338-3 PMID: 30638856
  73. Carpenter TO, Whyte MP, Imel EA, et al. Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med 2018; 378(21): 1987-98. doi: 10.1056/NEJMoa1714641 PMID: 29791829
  74. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: A randomised, active-controlled, open-label, phase 3 trial. Lancet 2019; 393(10189): 2416-27. doi: 10.1016/S0140-6736(19)30654-3 PMID: 31104833
  75. Padidela R, Whyte MP, Glorieux FH, et al. Patient-reported outcomes from a randomized, active-controlled, open-label, phase 3 trial of burosumab versus conventional therapy in children with X-Linked hypophosphatemia. Calcif Tissue Int 2021; 108(5): 622-33. doi: 10.1007/s00223-020-00797-x PMID: 33484279
  76. Linglart A, Imel EA, Whyte MP, et al. Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children with X-Linked hypophosphatemia. J Clin Endocrinol Metab 2022; 107(3): 813-24. doi: 10.1210/clinem/dgab729 PMID: 34636899
  77. Martín Ramos S, Gil-Calvo M, Roldán V, Castellano Martínez A, Santos F. Positive response to one-year treatment with burosumab in pediatric patients with X-Linked hypophosphatemia. Front Pediatr 2020; 8: 48. doi: 10.3389/fped.2020.00048 PMID: 32133333

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