Login Register Cart 0
Generic placeholder image

Current Pediatric Reviews

Editor-in-Chief

ISSN (Print): 1573-3963
ISSN (Online): 1875-6336

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

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

Author(s): Fahad Aljuraibah*, Ibrahim Alalwan and Abdelhadi Habeb

Volume 20, Issue 4, 2024

Published on: 03 November, 2023

Page: [395 - 404] Pages: 10

DOI: 10.2174/0115733963206838231031102750

Price: $65

Abstract

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.

« Previous Next »
Graphical Abstract

[1]
Michigami T. Skeletal mineralization: Mechanisms and diseases. Ann Pediatr Endocrinol Metab 2019; 24(4): 213-9.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1007/s12018-016-9225-1]
[8]
Rathbun JC. Hypophosphatasia; A new developmental anomaly. AMA Am J Dis Child 1948; 75(6): 822-31.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1016/S0140-6736(55)91704-9] [PMID: 13222868]
[11]
Hypophosphatasia FD. Am J Med 1957; 22(5): 730-46.
[http://dx.doi.org/10.1016/0002-9343(57)90124-9] [PMID: 13410963]
[12]
Russell R. Excretion of inorganic pyrophosphate in hypophosphatasia. Lancet 1965; 286(7410): 461-4.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.1016/j.jbspin.2019.01.012] [PMID: 30711691]
[48]
Michigami T, Ozono K. Roles of phosphate in skeleton. Front Endocrinol 2019; 10: 180.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/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.
[http://dx.doi.org/10.3389/fped.2020.00048] [PMID: 32133333]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy