Experts' consensus on the management and treatment of individuals with X-linked hypophosphatemia across lifespan

doi:10.1007/s40618-025-02611-7

. 2025 Jul 1.

doi: 10.1007/s40618-025-02611-7. Online ahead of print.

Experts' consensus on the management and treatment of individuals with X-linked hypophosphatemia across lifespan

Baroncelli Giampiero I¹, Barale Marco², Brandi Maria Luisa^{3

4}, Camozzi Valentina⁵, Carrara Silvia⁶, Caruso Nicoletti Manuela⁷, Castellano Elena⁸, Cetani Filomena⁹, Comberiati Pasquale^{1

10}, Di Iorgi Natascia^{11

12}, Eller-Vainicher Cristina¹³, Emma Francesco¹⁴, Fintini Danilo¹⁵, Giannini Sandro¹⁶, Gianotti Laura¹⁷, Grandone Anna¹⁸, Grassi Giorgia¹³, Mora Stefano¹⁹, Palermo Andrea²⁰, Pigliaru Francesca²¹, Pitea Marco²², Procopio Massimo²³, Rochira Vincenzo^{24

25}, Ruggeri Rosaria Maddalena^{26

27}, Ruggiero Barbara¹⁴, Stagi Stefano^{28

29}, Vezzoli Giuseppe³⁰, Corbetta Sabrina^{31

32}

Affiliations

¹ Pediatric and Adolescent Endocrinology, Division of Pediatrics, Department of Obstetrics, Gynecology and Pediatrics, University Hospital, Pisa, Italy.
² Division of Oncological Endocrinology, Department of Medical Sciences, University of Turin, Turin, Italy.
³ F.I.R.M.O. Onlus Italian Foundation for the Research on Bone Diseases, Florence, Italy.
⁴ Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy.
⁵ Unit of Endocrinology, University Hospital of Padova, Padua, Italy.
⁶ Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
⁷ Department of Pediatrics, University of Catania, Catania, Italy.
⁸ Department of Endocrinology, Diabetes and Metabolism, Santa Croce and Carle Hospital, Cuneo, Italy.
⁹ Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy.
¹⁰ Department of Clinical and Experimental Medicine, Section of Paediatrics, University of Pisa, Pisa, Italy.
¹¹ Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹² Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa, Italy.
¹³ Unit of Endocrinology Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
¹⁴ Division of Nephrology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁵ Endocrinology and Diabetology Unit, Pediatric University Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁶ Department of Medicine (DIMED), UOC Clinica Medica 1, University of Padua, Padua, Italy.
¹⁷ Division of Endocrinology and Diabetology, Department of Medicine, Azienda Sanitaria Locale Cuneo 1, Cuneo, Italy.
¹⁸ Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy.
¹⁹ Laboratory of Pediatric Endocrinology, Department of Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy.
²⁰ Unit of Metabolic Bone and Thyroid Disorders, and Unit of Endocrinology and Diabetes, Fondazione Policlinico Campus Bio-Medico, Rome, Italy.
²¹ Endocrinology Unit, AOU Cagliari, Cagliari, Italy.
²² Pediatric Endocrinology Unit, Department of Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy.
²³ Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy.
²⁴ Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
²⁵ Endocrinology Unit, Department of Medical Specialties, Azienda Ospedaliero-Universitaria Policlinico di Modena, Ospedale Civile di Baggiovara, Modena, Italy.
²⁶ Endocrinology, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, Messina, Italy.
²⁷ Endocrinology Unit, Department of Medical Sciences, Azienda Ospedaliera Universitaria "G Martino" di Messina, Messina, Italy.
²⁸ Health Sciences Department, University of Florence, Florence, Italy.
²⁹ Auxo-Endocrinology Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
³⁰ Nephrology and Dialysis Unit, San Raffaele Scientific Institute, Vita Salute San Raffaele University, Milan, Italy.
³¹ Unit of Bone Metabolism Diseases and Diabetes, Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy. sabrina.corbetta@unimi.it.
³² Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy. sabrina.corbetta@unimi.it.

PMID: 40591205
DOI: 10.1007/s40618-025-02611-7

Experts' consensus on the management and treatment of individuals with X-linked hypophosphatemia across lifespan

Baroncelli Giampiero I et al. J Endocrinol Invest. 2025.

. 2025 Jul 1.

doi: 10.1007/s40618-025-02611-7. Online ahead of print.

Authors

Affiliations

¹ Pediatric and Adolescent Endocrinology, Division of Pediatrics, Department of Obstetrics, Gynecology and Pediatrics, University Hospital, Pisa, Italy.
² Division of Oncological Endocrinology, Department of Medical Sciences, University of Turin, Turin, Italy.
³ F.I.R.M.O. Onlus Italian Foundation for the Research on Bone Diseases, Florence, Italy.
⁴ Donatello Bone Clinic, Villa Donatello Hospital, Florence, Italy.
⁵ Unit of Endocrinology, University Hospital of Padova, Padua, Italy.
⁶ Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
⁷ Department of Pediatrics, University of Catania, Catania, Italy.
⁸ Department of Endocrinology, Diabetes and Metabolism, Santa Croce and Carle Hospital, Cuneo, Italy.
⁹ Department of Clinical and Experimental Medicine, Endocrine Unit, University of Pisa, Pisa, Italy.
¹⁰ Department of Clinical and Experimental Medicine, Section of Paediatrics, University of Pisa, Pisa, Italy.
¹¹ Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
¹² Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genoa, Italy.
¹³ Unit of Endocrinology Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
¹⁴ Division of Nephrology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁵ Endocrinology and Diabetology Unit, Pediatric University Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹⁶ Department of Medicine (DIMED), UOC Clinica Medica 1, University of Padua, Padua, Italy.
¹⁷ Division of Endocrinology and Diabetology, Department of Medicine, Azienda Sanitaria Locale Cuneo 1, Cuneo, Italy.
¹⁸ Department of Woman, Child and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples, Italy.
¹⁹ Laboratory of Pediatric Endocrinology, Department of Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy.
²⁰ Unit of Metabolic Bone and Thyroid Disorders, and Unit of Endocrinology and Diabetes, Fondazione Policlinico Campus Bio-Medico, Rome, Italy.
²¹ Endocrinology Unit, AOU Cagliari, Cagliari, Italy.
²² Pediatric Endocrinology Unit, Department of Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy.
²³ Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy.
²⁴ Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
²⁵ Endocrinology Unit, Department of Medical Specialties, Azienda Ospedaliero-Universitaria Policlinico di Modena, Ospedale Civile di Baggiovara, Modena, Italy.
²⁶ Endocrinology, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, Messina, Italy.
²⁷ Endocrinology Unit, Department of Medical Sciences, Azienda Ospedaliera Universitaria "G Martino" di Messina, Messina, Italy.
²⁸ Health Sciences Department, University of Florence, Florence, Italy.
²⁹ Auxo-Endocrinology Unit, Meyer Children's Hospital IRCCS, Florence, Italy.
³⁰ Nephrology and Dialysis Unit, San Raffaele Scientific Institute, Vita Salute San Raffaele University, Milan, Italy.
³¹ Unit of Bone Metabolism Diseases and Diabetes, Department of Endocrinology and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy. sabrina.corbetta@unimi.it.
³² Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy. sabrina.corbetta@unimi.it.

PMID: 40591205
DOI: 10.1007/s40618-025-02611-7

Abstract

Purpose: X-linked hypophosphatemia (XLH) is a rare hereditary skeletal disorder that may be very disabling and significantly impacting the quality of life throughout the lifespan. The aim of this document was to inform stakeholders about the lifelong impact, management, and treatment of individuals with XLH, especially focusing on the new therapeutic approach with burosumab.

Methods: From October 2023 to April 2024, a multidisciplinary working group of Italian experts on bone and mineral metabolism convened periodic online meetings. Statements were formulated identifying the most relevant studies, including randomized controlled trials, international guidelines based on GRADE criteria, and systematic reviews, and the experts' opinions.

Results: The panel of experts provided "consensus statements" on the clinical management of individuals with XLH across lifespan. Five main issues were identified: (1) clinical and biochemical diagnosis of individuals with XLH and monitoring of the progression of the disease; (2) effects of conventional treatment with phosphate supplements and active vitamin D metabolites; (3) effects of the treatment with burosumab; (4) multidisciplinary approach and management of individuals with XLH; (5) consensus statement for transition from pediatric to adult care in individuals with XLH.

Conclusion: Individuals with XLH often experience unmet needs throughout life; a multidisciplinary approach involving different specialists, is recommended. The new treatment with burosumab can provide an effective and safety therapeutic option in reducing the burden of the disease in both children and adults. Therefore, awareness about the XLH disease should be increased among stakeholders. The criteria and reimbursement policies of burosumab should be revised.

Keywords: Burosumab; Conventional treatment; FGF23; Osteomalacia; Rickets; XLH.

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Conflict of interest statement

Declarations. Conflict of interest: All Authors have no conflict of interest to declare.

References

1. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK (2009) Incidence and prevalence of nutritional and hereditary rickets in Southern Denmark. Eur J Endocrinol 160:491–497. https://doi.org/10.1530/EJE-08-0818 - DOI - PubMed
1. Rafaelsen S, Johansson S, Raeder H, Bjerknes R (2016) Hereditary hypophosphatemia in Norway: a retrospective population- based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 174:125–136. https://doi.org/10.1530/EJE-15-0515 - DOI - PubMed
1. Hawley S, Shaw NJ, Delmestri A, Prieto-Alhambra D, Cooper C, Pinedo-Villanueva R, Javaid MK (2020) Prevalence and mortality of individuals with X-linked hypophosphatemia: a united kingdom real-world data analysis. J Clin Endocrinol Metab 105:e871–e878. https://doi.org/10.1210/clinem/dgz203 - DOI - PubMed
1. Sandy JL, Nunez C, Wheeler BJ, Jefferies C, Morris A, Siafarikas A, Rodda CP, Simm P, Biggin A, Aum S, Elliot EJ, Munns CF (2023) Prevalence and characteristics of paediatric X-linked hypophosphataemia in Australia and New Zealand: results from the Australian and the New Zealand Paediatric Surveillance Units survey. Bone 173:116791. https://doi.org/10.1016/j.bone.2023.116791 - DOI - PubMed
1. Crisafulli S, Ingrasciotta Y, Vitturi G, Fontana A, L’Abbate L, Alessi Y, Ferraù F, Cantarutti L, Lazzerini D, Cannavò S, Trifirò G (2024) Epidemiological analysis to identify predictors of X-linked hypophosphatemia (XLH) diagnosis in an Italian pediatric population: the EPIX project. Endocrine 85:894–905. https://doi.org/10.1007/s12020-024-03793-5 - DOI - PubMed - PMC

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[1] Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK (2009) Incidence and prevalence of nutritional and hereditary rickets in Southern Denmark. Eur J Endocrinol 160:491–497. https://doi.org/10.1530/EJE-08-0818 - DOI - PubMed

[2] Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK (2009) Incidence and prevalence of nutritional and hereditary rickets in Southern Denmark. Eur J Endocrinol 160:491–497. https://doi.org/10.1530/EJE-08-0818 - DOI - PubMed

[3] Rafaelsen S, Johansson S, Raeder H, Bjerknes R (2016) Hereditary hypophosphatemia in Norway: a retrospective population- based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 174:125–136. https://doi.org/10.1530/EJE-15-0515 - DOI - PubMed

[4] Rafaelsen S, Johansson S, Raeder H, Bjerknes R (2016) Hereditary hypophosphatemia in Norway: a retrospective population- based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol 174:125–136. https://doi.org/10.1530/EJE-15-0515 - DOI - PubMed

[5] Hawley S, Shaw NJ, Delmestri A, Prieto-Alhambra D, Cooper C, Pinedo-Villanueva R, Javaid MK (2020) Prevalence and mortality of individuals with X-linked hypophosphatemia: a united kingdom real-world data analysis. J Clin Endocrinol Metab 105:e871–e878. https://doi.org/10.1210/clinem/dgz203 - DOI - PubMed

[6] Hawley S, Shaw NJ, Delmestri A, Prieto-Alhambra D, Cooper C, Pinedo-Villanueva R, Javaid MK (2020) Prevalence and mortality of individuals with X-linked hypophosphatemia: a united kingdom real-world data analysis. J Clin Endocrinol Metab 105:e871–e878. https://doi.org/10.1210/clinem/dgz203 - DOI - PubMed

[7] Sandy JL, Nunez C, Wheeler BJ, Jefferies C, Morris A, Siafarikas A, Rodda CP, Simm P, Biggin A, Aum S, Elliot EJ, Munns CF (2023) Prevalence and characteristics of paediatric X-linked hypophosphataemia in Australia and New Zealand: results from the Australian and the New Zealand Paediatric Surveillance Units survey. Bone 173:116791. https://doi.org/10.1016/j.bone.2023.116791 - DOI - PubMed

[8] Sandy JL, Nunez C, Wheeler BJ, Jefferies C, Morris A, Siafarikas A, Rodda CP, Simm P, Biggin A, Aum S, Elliot EJ, Munns CF (2023) Prevalence and characteristics of paediatric X-linked hypophosphataemia in Australia and New Zealand: results from the Australian and the New Zealand Paediatric Surveillance Units survey. Bone 173:116791. https://doi.org/10.1016/j.bone.2023.116791 - DOI - PubMed

[9] Crisafulli S, Ingrasciotta Y, Vitturi G, Fontana A, L’Abbate L, Alessi Y, Ferraù F, Cantarutti L, Lazzerini D, Cannavò S, Trifirò G (2024) Epidemiological analysis to identify predictors of X-linked hypophosphatemia (XLH) diagnosis in an Italian pediatric population: the EPIX project. Endocrine 85:894–905. https://doi.org/10.1007/s12020-024-03793-5 - DOI - PubMed - PMC

[10] Crisafulli S, Ingrasciotta Y, Vitturi G, Fontana A, L’Abbate L, Alessi Y, Ferraù F, Cantarutti L, Lazzerini D, Cannavò S, Trifirò G (2024) Epidemiological analysis to identify predictors of X-linked hypophosphatemia (XLH) diagnosis in an Italian pediatric population: the EPIX project. Endocrine 85:894–905. https://doi.org/10.1007/s12020-024-03793-5 - DOI - PubMed - PMC

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Experts' consensus on the management and treatment of individuals with X-linked hypophosphatemia across lifespan

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Experts' consensus on the management and treatment of individuals with X-linked hypophosphatemia across lifespan

Authors

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