Browsing by Author "Florenzano, Pablo"

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    Current Practices in Monitoring Children and Adults With X-linked Hypophosphatemia: A Global Survey of Expert Experience
    (Oxford University Press, 2025) Ali, Dalal S.; Alsarraf, Farah; Alrob, Hajar Abu; Alexander, R. Todd; Almoulia, Abdulrahman; Appelman-Dijkstra, Natasha M.; Beck-Nielsen, Signe Sparre; Biosse-Duplan, Martin; Brandi, Maria Luisa; Carpenter, Thomas O.; Chaussain, Catherine; Cohen-Solal, Martine; Crowley, Rachel K.; Dandurand, Karel; Florenzano, Pablo; Gagnon, Claudia; Goodyer, Paul; Grimbly, Chelsey; Hussein, Salma; Imel, Erik A.; Jan de Beur, Suzanne M.; Javaid, Muhammad K.; Lehman, Anna; Lems, Willem F.; Lewiecki, E. Michael; McDonnell, Ciara; Mirza, Reza D.; Morgante, Emmett; Portale, Anthony A.; Rhee, Yumie; Siggelkow, Heide; Tosi, Laura L.; Ward, Leanne M.; Guyatt, Gordon; Khan, Aliya A.; Medicine, School of Medicine
    This report provides recommendations for X-linked hypophosphatemia (XLH) monitoring based on current monitoring practices of experts in the management of XLH in children (<18 years) and adults. We surveyed 43 international experts in XLH to determine their monitoring practices for children and adults with XLH, including pregnant and lactating women. In the initial evaluation of children and adults with XLH, experts consistently obtain a family history of XLH or hypophosphatemia, a history of fractures and dental infections, and assess pain through age-appropriate clinical interviews or caregiver reports. They measure height, weight, and blood pressure and conduct DNA analysis of multiple genes associated with hypophosphatemia including the PHEX gene. For children follow-up, experts arrange follow-up every 3 to 6 months assessing height, weight, and blood pressure and examining for skeletal deformities. Laboratory tests in children include serum phosphorus, corrected total/ionized calcium, alkaline phosphatase, renal function, and PTH and spot morning urine for calcium, creatinine, and phosphorus. During adult follow-up, experts assess patients every 6 to 12 months, with a clinical examination focused on skeletal deformities and joint involvement. The laboratory profile is completed at least once a year. In the presence of bone pain, experts conduct X-rays both in children and adults to evaluate for fractures or joint damage. With respect to nephrocalcinosis, renal ultrasound is suggested on an annual basis or less frequently when monitoring children and adults with XLH. Experts conduct a dental assessment at baseline and then every 6 to 12 months for all patients with XLH. The findings of the survey inform practice for assessing new patients with XLH, monitoring existing patients, and identifying areas for future research. All recommendations based on these practices are weak with very low-quality evidence.
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    Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia
    (Wiley, 2023) Jan de Beur, Suzanne M.; Minisola, Salvatore; Xia, Wei-bo; Abrahamsen, Bo; Body, Jean-Jacques; Brandi, Maria Luisa; Clifton-Bligh, Roderick; Collins, Michael; Florenzano, Pablo; Houillier, Pascal; Imanishi, Yasuo; Imel, Erik A.; Khan, Aliya A.; Zillikens, M. Carola; Fukumoto, Seiji; Medicine, School of Medicine
    Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.
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    Nephrocalcinosis and kidney function in children and adults with X-linked hypophosphatemia: baseline results from a large longitudinal study
    (Oxford University Press, 2024) Portale, Anthony A.; Ward, Leanne; Dahir, Kathryn; Florenzano, Pablo; Ing, Steven W.; Jan de Beur, Suzanne M.; Martin, Regina M.; Meza-Martinez, Adriana I.; Paloian, Neil; Ashraf, Ambika; Dixon, Bradley P.; Khan, Aliya; Langman, Craig; Chen, Angel; Wang, Christine; Scott Roberts, Mary; Tandon, P. K.; Bedrosian, Camille; Imel, Erik A.; Medicine, School of Medicine
    Background: In patients with X-linked hypophosphatemia (XLH), conventional therapy with oral phosphate salts and active vitamin D has been associated with nephrocalcinosis. However, the nature of the relationships among XLH, its treatment, nephrocalcinosis, and kidney function remain poorly understood. Methods: Renal ultrasounds were performed and glomerular filtration rates were estimated (eGFR) at baseline in burosumab-naïve patients with XLH who participated in burosumab clinical trials (NCT02181764, NCT02526160, NCT02537431, NCT02163577, NCT02750618, NCT02915705) or enrolled in the XLH Disease Monitoring Program (XLH-DMP; NCT03651505). In this cross-sectional analysis, patient, disease, and treatment characteristics were described among patients with and without nephrocalcinosis. Results: The analysis included 196 children (mean [SD] age 7.6 [4.0] yr) and 318 adults (40.3 [13.1] yr). Mean (SD) height z-score was -1.9 (1.2) for children and -2.3 (1.7) for adults. Nearly all children (97%) and adults (94%) had previously received conventional therapy. Nephrocalcinosis was detected in 22% of children and 38% of adults. In children, reduced eGFR <90 mL/min/1.73 m2 was more prevalent in those with nephrocalcinosis (25%) than in those without (11%), a finding that was not observed in adults. Children with nephrocalcinosis had lower mean values of TmP/GFR (p<.05), serum 1,25(OH)2D (p<.05), and eGFR (p<.001) and higher mean serum calcium concentrations (p<.05) than did those without nephrocalcinosis. Adults with nephrocalcinosis had lower mean serum phosphorus (p<.01) and 1,25(OH)2D (p<.05) concentrations than those without. Exploratory logistic regression analyses revealed no significant associations between the presence of nephrocalcinosis and other described patient or disease characteristics. Conclusions: Nephrocalcinosis was observed in nearly one-quarter of children and more than one-third of adults with XLH. Further study is needed to better understand the predictors and long-term consequences of nephrocalcinosis, with surveillance for nephrocalcinosis remaining important in the management of XLH.
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    Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Adult Patients With X-Linked Hypophosphatemia
    (Oxford University Press, 2025) Ali, Dalal S.; Mirza, Reza D.; Alsarraf, Farah; Hussein, Salma; Alrob, Hajar Abu; Appelman-Dijkstra, Natasha M.; Beck-Nielsen, Signe Sparre; Biosse-Duplan, Martin; Brandi, Maria Luisa; Carpenter, Thomas O.; Chaussain, Catherine; Cohen-Solal, Martine; Crowley, Rachel K.; Dandurand, Karel; Florenzano, Pablo; Fukumoto, Seiji; Gagnon, Claudia; Goodyer, Paul; Grasemann, Corinna; Imel, Erik A.; Jan de Beur, Suzanne M.; Lehman, Anna; Lewiecki, E. Michael; Morgante, Emmett; Ward, Leanne M.; Khan, Aliya A.; Guyatt, Gordon; Medicine, School of Medicine
    Context: Understanding the effects of burosumab compared to conventional therapy or no treatment on patient-important outcomes in adults with X-linked hypophosphatemia (XLH) is essential to guide evidence-based treatment recommendations. Objective: To examine the highest certainty evidence addressing the management of XLH in adults to inform treatment recommendations. Methods: We searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included randomized controlled trials (RCTs) and observational studies of individuals aged 18+ with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to no treatment or conventional therapy (phosphate and active vitamin D) and conventional therapy to no treatment were included. Two reviewers independently determined eligibility, extracted data, and assessed risk of bias (RoB). GRADE methodology was used to assess evidence certainty. Results: We screened 4114 records, after removing duplicates, and assessed 254 full texts. One RCT and 2 observational studies were eligible. The RCT of burosumab vs no treatment had low RoB. Burosumab probably improves pain from fracture/pseudofracture healing (moderate certainty) but has little or no impact on direct pain measures (moderate certainty). Burosumab may reduce the need for parathyroidectomy (low certainty) but has little or no impact on fatigue (high certainty), stiffness (moderate certainty), and mobility (low certainty) over 24 weeks. Burosumab may increase dental abscess risk (low certainty). Indirect evidence comparing burosumab to conventional therapy provided low certainty regarding burosumab vs conventional therapy. Two observational studies on conventional therapy vs no treatment had high RoB and very low certainty regarding the impact of conventional therapy on patient-important outcomes. Conclusion: No formal comparisons between burosumab and conventional therapy in adults exist. Evidence for conventional therapy vs no treatment is very uncertain. Our review highlights the need for more data on the long-term effects of burosumab and conventional therapy on patient-important outcomes in adult patients with XLH.
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    Systematic Review: Efficacy of Medical Therapy on Outcomes Important to Pediatric Patients With X-Linked Hypophosphatemia
    (Oxford University Press, 2025) Ali, Dalal S.; Mirza, Reza D.; Hussein, Salma; Alsarraf, Farah; Alexander, R. Todd; Alrob, Hajar Abu; Appelman-Dijkstra, Natasha M.; Biosse-Duplan, Martin; Brandi, Maria Luisa; Carpenter, Thomas O.; Chaussain, Catherine; Dandurand, Karel; Filler, Guido; Florenzano, Pablo; Fukumoto, Seiji; Grasemann, Corinna; Imel, Erik A.; Jan de Beur, Suzanne M.; Morgante, Emmett; Ward, Leanne M.; Khan, Aliya A.; Guyatt, Gordon; Medicine, School of Medicine
    Objective: To examine the evidence addressing the management of X-linked hypophosphatemia (XLH) in children to inform treatment recommendations. Methods: We searched Embase, MEDLINE, Web of Science, and Cochrane Central up to May 2023. Eligible studies included randomized controlled trials (RCTs) and observational studies of individuals younger than 18 years with clinically or genetically confirmed XLH. Manuscripts comparing burosumab to either no treatment or conventional therapy (phosphate and active vitamin D) or evaluating conventional therapy to no treatment were included. Two reviewers independently determined eligibility, extracted data, and assessed risk of bias (RoB). GRADE methodology was used to assess evidence certainty. Results: We screened 4114 records and assessed 254 full texts. One RCT and one post hoc study proved eligible when comparing burosumab to conventional therapy or no treatment. The open-label RCT was at high RoB, with certainty of evidence ranging from moderate to very low. Burosumab, compared to conventional therapy, probably prevents lower limb deformity and improves physical health quality of life (QoL) (moderate certainty). Burosumab may increase height and enhance the burden of symptoms related to chronic hypophosphatemia (low certainty). Burosumab probably increases treatment-emergent adverse events (moderate certainty) and may increase dental abscesses (low certainty). One observational study assessing conventional therapy vs no treatment was at high RoB, providing very low certainty evidence regarding the impact of conventional therapy on final height. Conclusion: Our review indicates that burosumab likely provides benefits to children by preventing lower limb deformity and improving physical health QoL while potentially increasing height. However, burosumab may also increase adverse events. Our review found limited evidence regarding the impact of conventional therapy compared to no treatment on final height. Further research is required to understand the long-term effect of medical therapy in children.
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    X-Linked Hypophosphatemia Management in Children: An International Working Group Clinical Practice Guideline
    (Oxford University Press, 2025) Ali, Dalal S.; Carpenter, Thomas O.; Imel, Erik A.; Ward, Leanne M.; Appelman-Dijkstra, Natasha M.; Chaussain, Catherine; Jan de Beur, Suzanne M.; Florenzano, Pablo; Alrob, Hajar Abu; Aldabagh, Rana; Alexander, R. Todd; Alsarraf, Farah; Beck-Nielsen, Signe Sparre; Biosse-Duplan, Martin; Crowley, Rachel K.; Dandurand, Karel; Filler, Guido; Friedlander, Lisa; Fukumoto, Seiji; Gagnon, Claudia; Goodyer, Paul; Grasemann, Corinna; Grimbly, Chelsey; Hussein, Salma; Javaid, Muhammad K.; Khan, Sarah; Khan, Aneal; Lehman, Anna; Lems, Willem F.; Lewiecki, E. Michael; McDonnell, Ciara; Mirza, Reza D.; Morgante, Emmett; Morrison, Archibald; Portale, Anthony A.; Rao, Christina; Rhee, Yumie; Rush, Eric T.; Siggelkow, Heide; Tetradis, Sotirios; Tosi, Laura; Guyatt, Gordon; Brandi, Maria Luisa; Khan, Aliya A.; Medicine, School of Medicine
    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.