X-Linked Hypophosphatemia Management in Children: An International Working Group Clinical Practice Guideline

Dalal S Ali¹, Thomas O Carpenter², Erik A Imel³, Leanne M Ward⁴, Natasha M Appelman-Dijkstra⁵, Catherine Chaussain⁶, Suzanne M Jan de Beur⁷, Pablo Florenzano⁸, Hajar Abu Alrob⁹, Rana Aldabagh¹⁰, R Todd Alexander¹¹, Farah Alsarraf¹, Signe Sparre Beck-Nielsen^{12

13}, Martin Biosse-Duplan^{6

14

15}, Rachel K Crowley¹⁶, Karel Dandurand¹⁷, Guido Filler¹⁸, Lisa Friedlander⁶, Seiji Fukumoto¹⁹, Claudia Gagnon^{20

21}, Paul Goodyer²², Corinna Grasemann²³, Chelsey Grimbly^{24

25}, Salma Hussein¹, Muhammad K Javaid²⁶, Sarah Khan²⁷, Aneal Khan²⁸, Anna Lehman²⁹, Willem F Lems³⁰, E Michael Lewiecki³¹, Ciara McDonnell^{32

33}, Reza D Mirza⁹, Emmett Morgante³⁴, Archibald Morrison³⁵, Anthony A Portale³⁶, Christina Rao³⁷, Yumie Rhee³⁸, Eric T Rush^{39

40}, Heide Siggelkow^{41

42}, Sotirios Tetradis⁴³, Laura Tosi⁴⁴, Gordon Guyatt^{9

45

46}, Maria Luisa Brandi⁴⁷, Aliya A Khan¹

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON, Canada L8S 4L8.
² Departments of Pediatrics (Endocrinology), and Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Department of Medicine and Pediatrics, Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁴ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
⁵ Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, 2300 ZA Leiden, The Netherlands.
⁶ Department of Oral Medicine, Faculty of Dentistry, UMR 1333, Université Paris Cité, 75006 Paris, France.
⁷ Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
⁸ Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile, 8320165 Santiago, Región Metropolitana, Chile.
⁹ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ONL8S 4L8, Canada.
¹⁰ Faculty of Dentistry, University of Toronto, Toronto, ON M5G 2L3, Canada.
¹¹ Faculty of Medicine & Dentistry, The University of Alberta, Edmonton, AB T6G 2R3, Canada.
¹² Centre for Rare Diseases, Aarhus University Hospital, 8200 Aarhus N, Denmark.
¹³ Department for Clinical Research, Aarhus University, 8200 Aarhus N, Denmark.
¹⁴ Institut Imagine, INSERM 1163, 75015 Paris, France.
¹⁵ Department of Oral Medicine, APHP, 75006 Paris, France.
¹⁶ Rare Disease Clinical Trial Network, University College Dublin, Dublin 4, D04 T6F4, Ireland.
¹⁷ Division of Internal Medicine, Endocrinology Division, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
¹⁸ Department of Pediatrics, Western University, London, ON N6A 3K7, Canada.
¹⁹ Department of Medicine, Tamaki-Aozora Hospital, 779-3125 Tokushima, Japan.
²⁰ CHU de Québec-Université Laval Research Centre, Endocrinology and Nephrology Axis, Quebec City, QC G1V 4G2, Canada.
²¹ Department of Medicine, Université Laval, Quebec City, QC, Canada G1V 0A6.
²² Research Institute of the McGill University Health Centre, Montreal, QC H3H 2L9, Canada.
²³ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, 44791 Bochum, Germany.
²⁴ Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
²⁵ Women and Children's Health Research Institute, Edmonton, AB T6G 1C9, Canada.
²⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7HE, UK.
²⁷ Trillium Health Partners, University of Toronto, Toronto, ON M5S 1A1, Canada.
²⁸ M.A.G.I.C. Clinic (Metabolics and Genetics in Canada), Calgary, AB T2E 7Z4, Canada.
²⁹ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³⁰ Department of Rheumatology, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands.
³¹ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM 87106, USA.
³² Department of Paediatric Endocrinology & Diabetes, Children's Health Ireland, Dublin D12 N512, Ireland.
³³ Department of Paediatrics, School of Medicine, University of Dublin, Trinity College, Dublin D02 PN40, Ireland.
³⁴ Department of Kinesiology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
³⁵ Citadel Oral and Facial Surgery, Halifax, NS B3L 4H7, Canada.
³⁶ Department of Pediatrics, University of California, San Francisco, CA 94115, USA.
³⁷ Department of Rehabilitation Services, Yale-New Haven Children's Hospital, New Haven, CT 06520, USA.
³⁸ Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
³⁹ Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO 64108, USA.
⁴⁰ Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108-2792, USA.
⁴¹ Department of Trauma, Orthopedics and Reconstructive Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany.
⁴² MVZ Endokrinologikum Goettingen, 37075 Goettingen, Germany.
⁴³ Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
⁴⁴ Department of Orthopedics, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
⁴⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
⁴⁶ MAGIC Evidence Ecosystem Foundation [www.magicevidence.org], Oslo 0456, Norway.
⁴⁷ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, 20132 Milan, Italy.

PMID: 39960858
PMCID: PMC12187519
DOI: 10.1210/clinem/dgaf093

Practice Guideline

X-Linked Hypophosphatemia Management in Children: An International Working Group Clinical Practice Guideline

Dalal S Ali et al. J Clin Endocrinol Metab. 2025.

. 2025 Jun 17;110(7):2055-2070.

doi: 10.1210/clinem/dgaf093.

Authors

Affiliations

¹ Division of Endocrinology and Metabolism, McMaster University, Hamilton, ON, Canada L8S 4L8.
² Departments of Pediatrics (Endocrinology), and Orthopedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Department of Medicine and Pediatrics, Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁴ Children's Hospital of Eastern Ontario, Department of Pediatrics, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
⁵ Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, 2300 ZA Leiden, The Netherlands.
⁶ Department of Oral Medicine, Faculty of Dentistry, UMR 1333, Université Paris Cité, 75006 Paris, France.
⁷ Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
⁸ Department of Endocrinology, School of Medicine Pontificia Universidad Católica de Chile, 8320165 Santiago, Región Metropolitana, Chile.
⁹ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ONL8S 4L8, Canada.
¹⁰ Faculty of Dentistry, University of Toronto, Toronto, ON M5G 2L3, Canada.
¹¹ Faculty of Medicine & Dentistry, The University of Alberta, Edmonton, AB T6G 2R3, Canada.
¹² Centre for Rare Diseases, Aarhus University Hospital, 8200 Aarhus N, Denmark.
¹³ Department for Clinical Research, Aarhus University, 8200 Aarhus N, Denmark.
¹⁴ Institut Imagine, INSERM 1163, 75015 Paris, France.
¹⁵ Department of Oral Medicine, APHP, 75006 Paris, France.
¹⁶ Rare Disease Clinical Trial Network, University College Dublin, Dublin 4, D04 T6F4, Ireland.
¹⁷ Division of Internal Medicine, Endocrinology Division, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
¹⁸ Department of Pediatrics, Western University, London, ON N6A 3K7, Canada.
¹⁹ Department of Medicine, Tamaki-Aozora Hospital, 779-3125 Tokushima, Japan.
²⁰ CHU de Québec-Université Laval Research Centre, Endocrinology and Nephrology Axis, Quebec City, QC G1V 4G2, Canada.
²¹ Department of Medicine, Université Laval, Quebec City, QC, Canada G1V 0A6.
²² Research Institute of the McGill University Health Centre, Montreal, QC H3H 2L9, Canada.
²³ Department of Pediatrics, Division of Rare Diseases, Katholisches Klinikum Bochum and Ruhr-University Bochum, 44791 Bochum, Germany.
²⁴ Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2R3, Canada.
²⁵ Women and Children's Health Research Institute, Edmonton, AB T6G 1C9, Canada.
²⁶ Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7HE, UK.
²⁷ Trillium Health Partners, University of Toronto, Toronto, ON M5S 1A1, Canada.
²⁸ M.A.G.I.C. Clinic (Metabolics and Genetics in Canada), Calgary, AB T2E 7Z4, Canada.
²⁹ Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.
³⁰ Department of Rheumatology, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands.
³¹ New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM 87106, USA.
³² Department of Paediatric Endocrinology & Diabetes, Children's Health Ireland, Dublin D12 N512, Ireland.
³³ Department of Paediatrics, School of Medicine, University of Dublin, Trinity College, Dublin D02 PN40, Ireland.
³⁴ Department of Kinesiology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
³⁵ Citadel Oral and Facial Surgery, Halifax, NS B3L 4H7, Canada.
³⁶ Department of Pediatrics, University of California, San Francisco, CA 94115, USA.
³⁷ Department of Rehabilitation Services, Yale-New Haven Children's Hospital, New Haven, CT 06520, USA.
³⁸ Endocrine Research Institute, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Korea.
³⁹ Division of Clinical Genetics, Children's Mercy Kansas City, Kansas City, MO 64108, USA.
⁴⁰ Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108-2792, USA.
⁴¹ Department of Trauma, Orthopedics and Reconstructive Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany.
⁴² MVZ Endokrinologikum Goettingen, 37075 Goettingen, Germany.
⁴³ Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095, USA.
⁴⁴ Department of Orthopedics, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
⁴⁵ Department of Medicine, McMaster University, Hamilton, ON, Canada L8S 4L8.
⁴⁶ MAGIC Evidence Ecosystem Foundation [www.magicevidence.org], Oslo 0456, Norway.
⁴⁷ Institute of Endocrine and Metabolic Sciences, Vita-Salute San Raffaele University and IRCCS, 20132 Milan, Italy.

PMID: 39960858
PMCID: PMC12187519
DOI: 10.1210/clinem/dgaf093

Abstract

Context: An International Working Group (IWG) developed new guidelines on the diagnosis, evaluation, management, and monitoring of X-linked hypophosphatemia (XLH) in children. Over the past 5 years, important advances have occurred in our understanding of the presentation, complications, and treatment of XLH.

Methods: A group of 50 international experts in XLH from Canada, the United States, Europe, Asia, and South America, along with methodology experts and a patient partner, held 18 teleconference meetings in 2023-2024. These meetings addressed key issues regarding diagnosing, evaluating, managing, and monitoring XLH in children. Two systematic reviews were conducted to examine the impact of burosumab compared to conventional therapy (phosphate salts and active vitamin D) or no therapy, and to assess the impact of conventional therapy vs no therapy on patient-important outcomes. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Additionally, narrative reviews were completed on XLH diagnosis and the role of genetic testing, and an expert clinical practice survey informed the monitoring recommendations.

Outcomes: An approach to establishing the diagnosis of XLH is presented. GRADEd recommendations were developed on treatment strategies for XLH in children. Monitoring recommendations, GRADEd as weak with very low certainty, were based on clinical practice survey of the IWG experts. The guidelines also addressed dental complications and proposed potential strategies to mitigate them.

Conclusion: These clinical practice guidelines provide an update of the current evidence on the diagnosis and management of XLH and provide a comprehensive guidance for multidisciplinary healthcare professionals involved in the care of children with XLH.

Keywords: X-linked hypophosphatemia (XLH); children; clinical practice guidelines; consensus; pediatrics; rickets.

PubMed Disclaimer

Figures

**Figure 2.**
GRADEd initial assessment recommendations in children with XL.

**Figure 3.**
GRADEd monitoring recommendations for follow-up in children with XLH.

See this image and copyright information in PMC

References

1. Baroncelli GI, Mora S. X-Linked hypophosphatemic rickets: multisystemic disorder in children requiring multidisciplinary management. Front Endocrinol (Lausanne). 2021;12:688309. - PMC - PubMed
1. Beck-Nielsen SS, Brixen K, Gram J, Brusgaard K. Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet. 2012;57(7):453‐458. - PubMed
1. Baroncelli GI, Angiolini M, Ninni E, Galli V, Saggese R, Giuca MR. Prevalence and pathogenesis of dental and periodontal lesions in children with X-linked hypophosphatemic rickets. Eur J Paediatr Dent. 2006;7(2):61‐66. - PubMed
1. Connor J, Olear EA, Insogna KL, et al. Conventional therapy in adults with X-linked hypophosphatemia: effects on enthesopathy and dental disease. J Clin Endocrinol Metab. 2015;100(10):3625‐3632. - PMC - PubMed
1. Ali DS, Mirza RD, Hussein S, 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. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

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

X-Linked Hypophosphatemia Management in Children: An International Working Group Clinical Practice Guideline

Affiliations

X-Linked Hypophosphatemia Management in Children: An International Working Group Clinical Practice Guideline

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous