RICKETS-LIKE DISEASES IN PEDIATRIC PRACTICE: CHALLENGES IN DIFFERENTIAL DIAGNOSIS AND CURRENT OPPORTUNITIES (A LITERATURE REVIEW AND CASE OBSERVATIONS)

  2. 2026
  3. RICKETS-LIKE DISEASES IN PEDIATRIC PRACTICE: CHALLENGES IN DIFFERENTIAL DIAGNOSIS AND CURRENT OPPORTUNITIES (A LITERATURE REVIEW AND CASE OBSERVATIONS)

Koniushevska A. A.

RICKETS-LIKE DISEASES IN PEDIATRIC PRACTICE: CHALLENGES IN DIFFERENTIAL DIAGNOSIS AND CURRENT OPPORTUNITIES (A LITERATURE REVIEW AND CASE OBSERVATIONS)

Show/Download

About the author:

Koniushevska A. A.

Heading:

LITERATURE REVIEWS

Type of article:

Scientific article

Annotation:

The article is devoted to the current state of the problem of hereditary rickets-like diseases in children, which are genetically determined disorders of phosphorus, calcium, and vitamin D metabolism. A literature review of the pathogenesis and clinical manifestations of rickets-like diseases is presented. The results of molecular genetic studies indicate that rickets-like diseases are characterized by considerable genetic heterogeneity. Therefore, definitive diagnosis is based on the identification of mutations in the corresponding genes, which remains both costly and time-consuming. Consequently, the differential diagnosis of these disorders is particularly important. Early diagnosis and timely initiation of pathogenetically targeted therapy may help slow the progression of rachitic skeletal deformities, promote positive growth dynamics, prevent complications, and reduce the risk of disability in affected children. The article discusses the main manifestations of rickets-like diseases in children, including severe progressive skeletal deformities and resistance to therapeutic doses of vitamin D. Differential diagnosis of the disorders most relevant to pediatric practice was performed, namely, vitamin D–resistant hypophosphatemic rickets, Vitamin D–dependent rickets, renal tubular acidosis, and Fanconi syndrome. The paper also provides a detailed overview of current treatment options for rickets-like diseases. For example, conventional combination therapy for hypophosphatemic rickets includes phosphate supplementation, active vitamin D metabolites, and, when indicated, growth hormone therapy and surgical correction of skeletal deformities. A novel treatment for X-linked hypophosphatemia, Burosumab, a fully human monoclonal antibody against fibroblast growth factor 23 that normalizes serum phosphate concentrations, is also described. Pharmacological treatment of renal tubular acidosis includes correction of acidosis, hypokalemia, hypocalcemia, and treatment of osteomalacia. Cases from the own clinical observations of a child with vitamin D–resistant hypophosphatemic rickets and a child with renal tubular acidosis are presented.

Tags:

children, classification, differential diagnosis, phosphate diabetes, renal tubular acidosis, rickets-like diseases

Bibliography:

  1. Baroncelli GI, Comberiati P, Aversa T, Baronio F, Cassio A, Chiarito M, et al. Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism. Front. Endocrinol. 2024;15:1383681. DOI: https://doi.org/10.3389/fendo.2024.1383681
  2. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018;2(378):1987-1998 DOI: https://doi.org/10.1056/NEJMoa1714641
  3. Vasquez-Rios G, Westrich Jr DJ, Isaac P, Edwards JC, Shieh S. Distal renal tubular acidosis and severe hypokalemia: a case report and review of the literature. J Med Case Rep. 2019;13(1):103. DOI: https://doi.org/10.1186/s13256-019-2056-1
  4. Bonner R, Hladik G. Renal Tubular Acidosis: Core Curriculum 2025. Am J Kidney Dis. 2025;85(4):501-512. DOI: https://doi.org/10.1053/j.ajkd.2024.08.014
  5. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2019;15(7):435-455. DOI: https://doi.org/10.1038/s41581-019-0152-5
  6. Elmonem MA, Veys KR, Soliman NA, van Dyck M, van den Heuvel LP, Levtchenko E. Cystinosis: a review. Orphanet J of Rare Dis. 2016;11:47. DOI: https://doi.org/10.1186/s13023-016-0426-y
  7. Santos F, Ordonez FA, Claramunt-Taberner D, GilPena H. Clinical and laboratory approaches in the diagnosis of renal tubular acidosis. Pediatr Nephrol. 2015;30(12):2099-2107. DOI: https://doi.org/10.1007/s00467-015-3083-9
  8. Razali NN, Hwu TT, Thilakavathy K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets. J Pediatr Endocrinol Metab. 2015;28(9-10):1009-1017. DOI: https://doi.org/10.1515/jpem-2014-0366
  9. Mohebbi N, Wagner CA. Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis. J Nephrol. 2018; 31(4):511- 522. DOI: https://doi.org/10.1007/s40620-017-0447-1
  10. Jo HY, Shin JH, Kim HY, Kim YM, Lee H, Bae MH, et al. Identification of a novel variant in the PHEX gene using targeted gene panel sequencing in a 24-month-old boy with hypophosphatemic rickets. Ann Pediatr Endocrinol Metab. 2020; 25(1):63-67. DOI: https://doi.org/10.6065/apem.2020.25.1.63
  11. Chinoy A, Padidela R. Refractory Rickets. Indian J Pediatr. 2023;90(6):574-581. DOI: https://doi.org/10.1007/s12098-023-04538-4
  12. Kinoshita Y, Fukumoto S. X–Linked Hypophosphatemia and FGF23–Related Hypophosphatemic Diseases: Prospect for New Treatment. Endocr Rev. 2018;39(3):274-291. DOI: https://doi.org/10.1210/er.2017-00220
  13. Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016;12(4):233-246. DOI: https://doi.org/10.1038/nrendo.2016.14
  14. Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, et al. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. Clin Endocrinol Metab. 2016;101(1):334-42. DOI: https://doi.org/10.1210/jc.2015-3462
  15. Ito N, Peña AS, Perano S, Atkins GJ, Findlay DM, Couper JJ. First Australian report of vitamin D-dependent rickets type I. Med J Aust. 2014;201(7):420-421.
  16. Bagga A, Sinha A. Renal Tubular Acidosis. Indian J Pediatr. 2020;87(9):733-744. DOI: https://doi.org/10.1007/s12098-020-03318-8
  17. Ito N, Hidaka N, Kato H. The pathophysiology of hypophosphatemia. Best Pract Res Clin Endocrinol Metab. 2024;38(2):101851. DOI: https://doi.org/10.1016/j.beem.2023.101851
  18. Oh S, Sandy JL, Munns CF, Simm PJ, Siafarikas A, Collins L. Hearing impairment in X-linked hypophosphatemia: a review. JBMR Plus. 2025;9(5):v14–v29. DOI: https://doi.org/10.1093/jbmrpl/ziaf062
  19. Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta Gema, et al. FGF23 and its role in X-linked hypophosphatemia- related morbidity. Orphanet J Rare Dis. 2019;14(1):58. DOI: https://doi.org/10.1186/s13023-019-1014-8
  20. Fuente R, Gil–Peña H, Claramunt–Taberner D, Hernández O, Fernández-Iglesias A, Alonso-Durán L, et al. X–linked hypophosphatemia and growth. Rev Endocr Metab Disord. 2017;18(1):107-115. DOI: https://doi.org/10.1007/s11154-017-9408-1
  21. Fuente R, Gil-Peña H, Claramunt-Taberner D, Hernández O, Fernández-Iglesias A, Alonso-Durán L, et al. X-linked hypophosphatemia and growth. Rev Endocr Metab Disord. 2019;20(1):127. DOI: https://doi.org/10.1007/s11154-017-9435-y
  22. Bosman A, Appelman-Dijkstra NM, Boot AM, de Borst MH, van de Ven AC, de Jongh RT, et al. Disease Manifestations and Complications in Dutch X-Linked Hypophosphatemia Patients. Calcif Tissue Int. 2024;114(3):255-266. DOI: https://doi.org/10.1007/s00223-023-01172-2
  23. Bergwitz C, Miyamoto KI. Hereditary hypophosphatemic rickets with hypercalciuria: pathophysiology, clinical presentation, diagnosis and therapy. Pflugers Arch. 2019;471(1):149-163. DOI: https://doi.org/10.1007/s00424-018-2184-2
  24. Dhir G, Dong Li, Hakonarson H, Levine MA. Late-onset hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to mutation of SLC34A3/NPT2c. Bone. 2017;97:15-19. DOI: https://doi.org/10.1016/j.bone.2016.12.001
  25. Stürznickel J, Heider F, Delsmann A, Gödel M, Grünhagen J, Huber TB, et al. Clinical Spectrum of Hereditary Hypophosphatemic Rickets With Hypercalciuria (HHRH). JBMR. 2022;37(8):1580-1591. DOI: https://doi.org/10.1002/jbmr.4630
  26. Haffner D, Emma F, Seefried L, Högler W, Javaid KM, Bockenhauer D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol. 2025;21(5):330-354. DOI: https://doi.org/10.1038/s41581-024-00926-x
  27. Imel EA, White KE. Pharmacological management of X-linked hypophosphataemia. Br J Clin Pharmacol. 2019;85(6):1188-1198. DOI: https://doi.org/10.1111/bcp.13763
  28. Ali DS, Carpenter TO, Imel EA, Ward LM, Appelman-Dijkstra NM, Chaussain C, et al. X-Linked Hypophosphatemia Management in Children: An International Working Group Clinical Practice Guideline. J Clin Endocrinol Metab. 2025;110(7):2055-2070. DOI: https://doi.org/10.1210/clinem/dgaf093
  29. Ackah SA, Imel EA. Approach to Hypophosphatemic Rickets. J Clin Endocrinol Metab. 2022;108(1):209-220. DOI: https://doi.org/10.1210/clinem/dgac488
  30. Ali DS, Mirza RD, Hussein S, Alsarraf F, Alexander RT, Abu Alrob H, et al. Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Pediatric Patients With X-Linked Hypophosphatemia. J Clin Endocrinol Metab. 2025;110(5):1205-1217. DOI: https://doi.org/10.1210/clinem/dgaf011
  31. Smith S, Remmington T. Recombinant growth hormone therapy for X-linked hypophosphatemia in children. Cochrane Database Syst Rev. 2021;10(10):CD004447. DOI: https://doi.org/10.1002/14651858.CD004447.pub3
  32. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, 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):2416-2427. DOI: https://doi.org/10.1016/S0140-6736(19)30654-3
  33. Wang S, Wang X, He M, Li Y, Xiao M, Ma H. Efficacy and Safety of Burosumab in X-linked Hypophosphatemia. J Clin Endocrinol Metab. 2023;109(1):293-302. DOI: https://doi.org/10.1210/clinem/dgad440
  34. Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018;378(21):1987-1998. DOI: https://doi.org/10.1056/NEJMoa1714641
  35. Whyte MP, Carpenter TO, Gottesman GS, Mao M, Skrinar A, San Martin J, 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):189-199. DOI: https://doi.org/10.1016/S2213-8587(18)30338-3
  36. Horn A, Wright J, Bockenhauer D, Van’t Hoff W, Eastwood DM. The orthopaedic management of lower limb deformity in hypophosphataemic rickets. J. Child. Orthop. 2017;11(4):298-305. DOI: https://doi.org/10.1302/1863-2548.11.170003
  37. Palmer BF, Kelepouris E, Clegg DJ. Renal Tubular Acidosis and Management Strategies: A Narrative Review. Adv Ther. 2021;38(2):949- 968. DOI: https://doi.org/10.1007/s12325-020-01587-5
  38. Trepiccione F, Prosperi F, de la Motte LR, Hübner CA, Chambrey R, Eladari D, et al. New Findings on the Pathogenesis of Distal Renal Tubular Acidosis. Kidney Dis (Basel). 2017;3(3):98-105. DOI: https://doi.org/10.1159/000478781
  39. Fearn A, Allison B, Rice SJ, Edwards N, Halbritter J, Bourgeois S, et al. Clinical, biochemical, and pathophysiological analysis of SLC34A1 mutations. Physiol Rep. 2018;6(12):e13715. DOI: https://doi.org/10.14814/phy2.13715
  40. Bichard L, Toh D. Ibuprofen-induced distal (type 1) renal tubular acidosis and hypokalaemia: the dangers of ibuprofen-codeine combination over-thecounter preparations. Intern Med J. 2017;47(6):707-709. DOI: https://doi.org/10.1111/imj.13436
  41. Ho K, Dokouhaki P, McIsaac M, Prasad B. Renal tubular acidosis as the initial presentation of Sjogren’s syndrome. BMJ Case Rep. 2019;12:e230402. DOI: https://doi.org/10.1136/bcr-2019-230402
  42. Üsküdar Cansu D, Cansu GB, Güvenir S, Korkmaz C. Hyperkalemia in type 4 renal tubular acidosis associated with systemic lupus erythematosus. Rheumatol Int. 2020;40(11):1895-1901. DOI: https://doi.org/10.1007/s00296-020-04546-z
  43. Watanabe T. Improving outcomes for patients with distal renal tubular acidosis: recent advances and challenges ahead. Pediatric Health Med Ther. 2018;9:181-190. DOI: https://doi.org/10.2147/PHMT.S174459
  44. Mohebbi N, Wagner CA. Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis. J Nephrol. 2018;31(4):511-22. DOI: https://doi.org/10.1007/s40620-017-0447-1
  45. Fuster DG, Moe OW. Incomplete distal renal tubular acidosis and kidney stones. Adv Chronic Kidney Dis. 2018;25(4):366-374. DOI: https://doi.org/10.1053/j.ackd.2018.05.007

Publication of the article:

«Bulletin of problems biology and medicine», 2026 Issue 2, 181, 84-98 pages, index UDC 616.71-007.15-039.4-053.2-079.4-085

DOI:

10.29254/2077-4214-2026-2-181-84-98

2026 Issue 2, 181
children classification differential diagnosis phosphate diabetes renal tubular acidosis rickets-like diseases
27.05.2026
Was this article helpful?
0
1

Leave a Reply

Your email address will not be published. Required fields are marked *


The reCAPTCHA verification period has expired. Please reload the page.