Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

doi:10.1038/s41581-024-00926-x

Review

. 2025 May;21(5):330-354.

doi: 10.1038/s41581-024-00926-x. Epub 2025 Jan 15.

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

Dieter Haffner^{1

2}, Francesco Emma³, Lothar Seefried⁴, Wolfgang Högler⁵, Kassim M Javaid⁶, Detlef Bockenhauer^{7

8}, Justine Bacchetta⁹, Deborah Eastwood^{10

11}, Martin Biosse Duplan^{12

13

14}, Dirk Schnabel¹⁵, Philippe Wicart^{14

16

17}, Gema Ariceta¹⁸, Elena Levtchenko¹⁹, Pol Harvengt²⁰, Martha Kirchhoff²¹, Oliver Gardiner²⁰, Federico Di Rocco²², Catherine Chaussain^{12

13

14}, Maria Luisa Brandi²³, Lars Savendahl²⁴, Karine Briot^{14

17

25

26}, Peter Kamenický^{14

27}, Lars Rejnmark²⁸, Agnès Linglart^{14

29}

Affiliations

¹ Department of Paediatric Kidney, Liver, Metabolic and Neurological Diseases, Hannover Medical, School, Hannover, Germany. haffner.dieter@mh-hannover.de.
² Center for Congenital Kidney Diseases, Center for Rare Diseases, Hannover Medical School, Hannover, Germany. haffner.dieter@mh-hannover.de.
³ Division of Nephrology, Children's Hospital Bambino Gesù, IRCCs, Rome, Italy.
⁴ Clinical Trial Unit, Orthopedic Institute, Koenig-Ludwig-Haus, University of Würzburg, Würzburg, Germany.
⁵ Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria.
⁶ Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK.
⁷ University College London, Department of Renal Medicine and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁸ Department of Paediatric Nephrology, University Hospitals Leuven, Katholic University of Leuven, Leuven, Belgium.
⁹ Paediatric Nephrology Rheumatology and Dermatology Unit, Hospices Civils de Lyon, INSERM1033 Research Unit, Lyon, France.
¹⁰ Department of Orthopaedics, Great Ormond Street Hospital for Children, London, UK.
¹¹ The Catterall Unit, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK.
¹² Université Paris Cité, Dental School, Montrouge, France.
¹³ APHP, Department of Odontology, Bretonneau Hospital, Paris, France.
¹⁴ APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France.
¹⁵ Center for Chronic Sick Children, Paediatric Endocrinology, Charité-University Medicine, Berlin, Germany.
¹⁶ APHP, Department of Paediatric Orthopedic Surgery, Necker - Enfants Malades University Hospital, Paris, France.
¹⁷ Université Paris Cité, Paris, France.
¹⁸ Department of Paediatric Nephrology, University Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain.
¹⁹ Amsterdam University Medical Centre, Amsterdam, The Netherlands.
²⁰ International XLH Alliance, London, United Kingdom.
²¹ Phosphatdiabetes e.V., German Patient Association for XLH, Lippstadt, Germany.
²² Paediatric Neurosurgery, Hôpital Femme Mère Enfant, Centre de Référence Craniosténoses, Université de Lyon, INSERM 1033, Lyon, France.
²³ San Raffaele University Hospital, Milan, Italy.
²⁴ Paediatric Endocrinology Unit, Karolinska University Hospital, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
²⁵ APHP, Department of Rheumatology, Cochin Hospital, Paris, France.
²⁶ INSERM UMR-1153, Paris, France.
²⁷ Université Paris Saclay, Inserm, AP-HP, Physiologie et Physiopathologie Endocriniennes, Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre Paris Saclay, Le Kremlin Bicêtre, France.
²⁸ Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
²⁹ Université Paris Saclay, Inserm, AP-HP, Physiologie et Physiopathologie Endocriniennes, Service Endocrinologie et diabète de l'enfant, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France.

PMID: 39814982
DOI: 10.1038/s41581-024-00926-x

Review

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

Dieter Haffner et al. Nat Rev Nephrol. 2025 May.

. 2025 May;21(5):330-354.

doi: 10.1038/s41581-024-00926-x. Epub 2025 Jan 15.

Authors

Affiliations

¹ Department of Paediatric Kidney, Liver, Metabolic and Neurological Diseases, Hannover Medical, School, Hannover, Germany. haffner.dieter@mh-hannover.de.
² Center for Congenital Kidney Diseases, Center for Rare Diseases, Hannover Medical School, Hannover, Germany. haffner.dieter@mh-hannover.de.
³ Division of Nephrology, Children's Hospital Bambino Gesù, IRCCs, Rome, Italy.
⁴ Clinical Trial Unit, Orthopedic Institute, Koenig-Ludwig-Haus, University of Würzburg, Würzburg, Germany.
⁵ Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria.
⁶ Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK.
⁷ University College London, Department of Renal Medicine and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁸ Department of Paediatric Nephrology, University Hospitals Leuven, Katholic University of Leuven, Leuven, Belgium.
⁹ Paediatric Nephrology Rheumatology and Dermatology Unit, Hospices Civils de Lyon, INSERM1033 Research Unit, Lyon, France.
¹⁰ Department of Orthopaedics, Great Ormond Street Hospital for Children, London, UK.
¹¹ The Catterall Unit, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK.
¹² Université Paris Cité, Dental School, Montrouge, France.
¹³ APHP, Department of Odontology, Bretonneau Hospital, Paris, France.
¹⁴ APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France.
¹⁵ Center for Chronic Sick Children, Paediatric Endocrinology, Charité-University Medicine, Berlin, Germany.
¹⁶ APHP, Department of Paediatric Orthopedic Surgery, Necker - Enfants Malades University Hospital, Paris, France.
¹⁷ Université Paris Cité, Paris, France.
¹⁸ Department of Paediatric Nephrology, University Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain.
¹⁹ Amsterdam University Medical Centre, Amsterdam, The Netherlands.
²⁰ International XLH Alliance, London, United Kingdom.
²¹ Phosphatdiabetes e.V., German Patient Association for XLH, Lippstadt, Germany.
²² Paediatric Neurosurgery, Hôpital Femme Mère Enfant, Centre de Référence Craniosténoses, Université de Lyon, INSERM 1033, Lyon, France.
²³ San Raffaele University Hospital, Milan, Italy.
²⁴ Paediatric Endocrinology Unit, Karolinska University Hospital, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
²⁵ APHP, Department of Rheumatology, Cochin Hospital, Paris, France.
²⁶ INSERM UMR-1153, Paris, France.
²⁷ Université Paris Saclay, Inserm, AP-HP, Physiologie et Physiopathologie Endocriniennes, Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre Paris Saclay, Le Kremlin Bicêtre, France.
²⁸ Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
²⁹ Université Paris Saclay, Inserm, AP-HP, Physiologie et Physiopathologie Endocriniennes, Service Endocrinologie et diabète de l'enfant, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France.

PMID: 39814982
DOI: 10.1038/s41581-024-00926-x

Erratum in

Publisher Correction: Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia.
Haffner D, Emma F, Seefried L, Högler W, Javaid KM, Bockenhauer D, Bacchetta J, Eastwood D, Biosse Duplan M, Schnabel D, Wicart P, Ariceta G, Levtchenko E, Harvengt P, Kirchhoff M, Gardiner O, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenický P, Rejnmark L, Linglart A. Haffner D, et al. Nat Rev Nephrol. 2025 May;21(5):355. doi: 10.1038/s41581-025-00939-0. Nat Rev Nephrol. 2025. PMID: 39905262 No abstract available.

Abstract

X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients.

PubMed Disclaimer

Conflict of interest statement

Competing interests: J.B. and L.S. receive support for research and consultancy from Kyowa Kirin. A.L., M.B.D., L.R. and C.C. receive research support from Kyowa Kirin. D.H. receives research support and speaker and consultant fees from Kyowa Kirin. The institution of A.L. (AP-HP) receives her speaker and consultant fees from Kyowa Kirin. G.A. receives speaker and consultant fees from Kyowa Kirin. F.E., E.L., P.K., K.B., D.S., M.L.B. and K.B. receive consultation fees from Kyowa Kirin. All other authors declare no competing interests.

Cited by

Prevalence of enthesopathies in X-linked hypophosphatemia: an explorative ultrasound study.
Bachfischer L, Behanova M, Rath E, Meng S, Mittelbach A, Haschka J, Dechat T, Raimann A, Mindler G, Uyanik G, Zwerina J, Kocijan R. Bachfischer L, et al. JBMR Plus. 2025 Jul 7;9(9):ziaf113. doi: 10.1093/jbmrpl/ziaf113. eCollection 2025 Sep. JBMR Plus. 2025. PMID: 40800666 Free PMC article.
The Diagnosis and Therapy of XLH.
Böckmann I, Haffner D. Böckmann I, et al. Calcif Tissue Int. 2025 Apr 28;116(1):66. doi: 10.1007/s00223-025-01374-w. Calcif Tissue Int. 2025. PMID: 40295317 Free PMC article. Review.
A case report of X-linked hypophosphatemia combined with primary hyperparathyroidism.
Wu Y, Yang M, Zhang Y, Wang Q. Wu Y, et al. Front Endocrinol (Lausanne). 2025 Jul 29;16:1634377. doi: 10.3389/fendo.2025.1634377. eCollection 2025. Front Endocrinol (Lausanne). 2025. PMID: 40801029 Free PMC article.
The genetic polymorphism of XPR1 associated with Fanconi syndrome in Chinese patients with X-linked hypophosphatemia.
Han S, Li X, Liu W, Chi Y, Jiajue R, Fu Z, Pang Q, Wang O, Li M, Xing X, Jiang Y, Xia W. Han S, et al. J Endocrinol Invest. 2025 Aug 6. doi: 10.1007/s40618-025-02678-2. Online ahead of print. J Endocrinol Invest. 2025. PMID: 40768184
Experts' consensus on the management and treatment of individuals with X-linked hypophosphatemia across lifespan.
I BG, Marco B, Luisa BM, Valentina C, Silvia C, Manuela CN, Elena C, Filomena C, Pasquale C, Natascia DI, Cristina EV, Francesco E, Danilo F, Sandro G, Laura G, Anna G, Giorgia G, Stefano M, Andrea P, Francesca P, Marco P, Massimo P, Vincenzo R, Maddalena RR, Barbara R, Stefano S, Giuseppe V, Sabrina C. I BG, et al. J Endocrinol Invest. 2025 Jul 1. doi: 10.1007/s40618-025-02611-7. Online ahead of print. J Endocrinol Invest. 2025. PMID: 40591205

See all "Cited by" articles

References

1. Beck-Nielsen, S. S., Brock-Jacobsen, B., Gram, J., Brixen, K. & Jensen, T. K. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur. J. Endocrinol. 160, 491–497 (2009). - PubMed - DOI
1. Endo, I. et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr. J. 62, 811–816 (2015). - PubMed - DOI
1. Rafaelsen, S., Johansson, S., Ræder, H. & Bjerknes, R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur. J. Endocrinol. 174, 125–136 (2016). - PubMed - DOI
1. Martin, A., David, V. & Quarles, L. D. Regulation and function of the FGF23/klotho endocrine pathways. Physiol. Rev. 92, 131–155 (2012). - PubMed - DOI
1. Carpenter, T. O., Imel, E. A., Holm, I. A., Jan de Beur, S. M. & Insogna, K. L. A clinician’s guide to X-linked hypophosphatemia. J. Bone Min. Res. 26, 1381–1388 (2011). - DOI

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Miscellaneous
- NCI CPTAC Assay Portal

[1] Beck-Nielsen, S. S., Brock-Jacobsen, B., Gram, J., Brixen, K. & Jensen, T. K. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur. J. Endocrinol. 160, 491–497 (2009). - PubMed - DOI

[2] Beck-Nielsen, S. S., Brock-Jacobsen, B., Gram, J., Brixen, K. & Jensen, T. K. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur. J. Endocrinol. 160, 491–497 (2009). - PubMed - DOI

[3] Endo, I. et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr. J. 62, 811–816 (2015). - PubMed - DOI

[4] Endo, I. et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr. J. 62, 811–816 (2015). - PubMed - DOI

[5] Rafaelsen, S., Johansson, S., Ræder, H. & Bjerknes, R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur. J. Endocrinol. 174, 125–136 (2016). - PubMed - DOI

[6] Rafaelsen, S., Johansson, S., Ræder, H. & Bjerknes, R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur. J. Endocrinol. 174, 125–136 (2016). - PubMed - DOI

[7] Martin, A., David, V. & Quarles, L. D. Regulation and function of the FGF23/klotho endocrine pathways. Physiol. Rev. 92, 131–155 (2012). - PubMed - DOI

[8] Martin, A., David, V. & Quarles, L. D. Regulation and function of the FGF23/klotho endocrine pathways. Physiol. Rev. 92, 131–155 (2012). - PubMed - DOI

[9] Carpenter, T. O., Imel, E. A., Holm, I. A., Jan de Beur, S. M. & Insogna, K. L. A clinician’s guide to X-linked hypophosphatemia. J. Bone Min. Res. 26, 1381–1388 (2011). - DOI

[10] Carpenter, T. O., Imel, E. A., Holm, I. A., Jan de Beur, S. M. & Insogna, K. L. A clinician’s guide to X-linked hypophosphatemia. J. Bone Min. Res. 26, 1381–1388 (2011). - DOI

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

Affiliations

Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous

Erratum in

Abstract

Conflict of interest statement

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Miscellaneous