X-linked hypophosphatemia (XLH) is a rare disorder of renal phosphate wasting and dysregulated active vitamin D metabolism, ultimately presenting as rickets and osteomalacia, among other manifestations. Lower extremity deformity (genu valgum and/or varum) is frequent in this pediatric population. Despite prompt active vitamin D and phosphate supplementation (active D/Pi), many patients require corrective surgery for lower limb malformation. Burosumab has demonstrated improvements in lower limb malalignment in children with XLH in several studies. We expand on those reports by assessing mechanical femoral tibial angle (mFTA) change in patients enrolled in the XLH Disease Monitoring Program (DMP), (NCT03651505) to determine the impact of initiating burosumab treatment after a history of active D/Pi. Included patients had either switched from active D/Pi to burosumab treatment at the discretion of their treating physician or as part of a burosumab clinical trial, or remained on active D/Pi through Year 3 of the DMP. Year 3 radiographs were compared with baseline to assess mFTA change and gauge improvement. Additional multivariate factor analysis examined 24 attributes to determine which had the greatest association with mFTA change. Change in mFTA was assessed for each limb independently. A greater proportion of limbs of patients switching from active D/Pi to burosumab had improved mFTA compared with those remaining on active D/Pi (p < .023). Odds ratios comparing limbs that improved to those that did not showed that switching to burosumab yields a significantly greater chance of improvement than continuing active D/Pi (OR [95% CI]: 4.38 [1.09-17.50]; p = .0469). Factor analysis identified younger age at burosumab initiation (p = .001) and lower baseline height Z-score (p = .006) as being significantly associated with greater change in mFTA Z-score. This study shows that switching to burosumab significantly improves lower limb malalignment in children with XLH over benefits conferred by active D/Pi, with early burosumab initiation providing the greatest benefit.

X-linked hypophosphatemia (XLH) is a rare, genetic, progressive, lifelong disorder caused by pathogenic variants in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene, resulting in excess fibroblast growth factor 23 (FGF23) and consequent renal phosphate wasting. Chronic hypophosphatemia leads to deficits of the musculoskeletal system affecting bone, muscle, joint, and dental health. XLH treatments include oral phosphate and active vitamin D—which are associated with a burdensome dosing regimen, gastrointestinal disturbances, hyperparathyroidism, and nephrocalcinosis—or burosumab, a fully human anti-FGF23 antibody. Randomized clinical trials (RCTs) demonstrated burosumab to be well tolerated and efficacious in improving serum phosphate, rickets, bone turnover, and patient-reported outcomes. However, there are limited data on the natural history of XLH or real-world comparisons of the safety, effectiveness, and long-term outcomes of XLH treatments. Advancing Patient Evidence in XLH (APEX) is a global data unification project aiming to describe the burden and lifelong progression of XLH, collect real-world data on treatment effectiveness and safety, and investigate regional differences in treatment outcomes. Participants from three observational, noninterventional, retrospective and prospective, multicenter, longitudinal (10-year) studies of patients with XLH will be included: XLH Disease Monitoring Program (NCT03651505), International XLH Registry (NCT03193476), and SUNFLOWER (NCT03745521). Data collected in the Americas, Europe, Israel, Japan, and South Korea will be processed to unify identical and similar data elements. Data unification will be an iterative process with a clinical and programming review, ensuring validity and accuracy. In this observational study, unified data involving approximately 2000 pediatric and adult participants with XLH will be analyzed to address research questions in an exploratory manner. Long-term observational studies and patient registries provide opportunities to generate real-world data and address knowledge gaps in rare diseases. APEX aims to improve clinical decision-making and practice by bridging evidence gaps that cannot be addressed by RCTs or regional registries.

PURPOSE:X-linked hypophosphatemia (XLH) is a rare, genetic, progressive, lifelong disorder caused by pathogenic variants in the PHEX gene, leading to excess fibroblast growth factor 23 (FGF23) and renal phosphate wasting. Advancing Patient Evidence in XLH (APEX) is a 10-year global data unification project that combines 3 regional observational studies (XLH Disease Monitoring Program [DMP], International XLH Registry [IXLHR], and SUNFLOWER). APEX aims to describe the burden and lifelong progression of XLH, to collect real-world data on treatment effectiveness and safety, and to investigate regional differences in treatment outcomes. METHODS:This was a baseline analysis of the characteristics and disease burden of a global group of patients with XLH. RESULTS:This analysis included 1556 participants (XLH DMP n = 598; IXLHR n = 736; SUNFLOWER n = 222), with 590 participants aged 0-12 years, 193 aged 13-17 years, and 773 aged ≥18 years. Overall, 66 % of participants were female. Family history of XLH and of a PHEX variant were reported for 55 % and 47 % of participants, respectively; 71 % of participants had a confirmed PHEX variant. Participants had reduced height, normal weight, and elevated body mass index compared with a reference population. Clinical histories demonstrated increasing prevalence of dental complications, fractures, and osteoarthritis with age. Median Z-scores for phosphate, tubular maximum reabsorption of phosphate to glomerular filtration rate, and urine calcium/creatinine ratio were below the scores for the reference population. CONCLUSION:This baseline analysis provides substantial information on the global characteristics and natural history of patients with XLH in the APEX program. REGISTRATION:ClinicalTrials.govNCT03651505 (registered August 24, 2018), NCT03193476 (registered June 13, 2017), NCT03745521 (registered November 6, 2018).

The guideline panel, comprising international experts in X-linked hypophosphatemia (XLH), patient partners from the XLH patient population, and guideline methodologists, held 18 teleconferences between January 2023 and July 2024 to develop comprehensive guidelines for the diagnosis and management of XLH in children and adults. For a subset of our questions, we utilized the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, assessed the certainty of evidence and formulated GRADEd recommendations. For these questions, the panelists and methodologists collaboratively framed PICO (Population, Intervention, Control, and Outcomes) questions and conducted four systematic reviews assessing the impact of medical therapy—using either burosumab or phosphate and active vitamin D—on patient-important outcomes in the XLH population as well as the impact of medical intervention compared to no treatment. We assessed the risk of bias and transparently generated summary of findings tables using MAGICApp. The panel developed three GRADEd treatment recommendations for adults and two for children. Each GRADEd recommendation was linked to an underlying body of evidence, reflecting judgments on the certainty of evidence, recommendation strength, values, preferences, and considerations of costs, feasibility, acceptability, and equity. Due to the paucity of evidence, the panel developed very low-quality GRADEd recommendations on monitoring patients with XLH based on an expert clinical practice survey. Using a rigorous narrative literature review, the panel developed non-GRADEd recommendations including guidance for pregnant women, patients with dental complications, and other areas where evidence is limited. This article summarizes the methodology utilized for the development of both GRADEd and non-GRADEd recommendations for patients with XLH.

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.

A 2-month-old female child presented with a low-trauma femoral fracture, low bone mass, bowing of long bones, loss of height of a thoracic vertebra, and Wormian bones. Exome sequencing revealed the presence of a novel heterozygous 4006G > C pG1336R mutation in exon 25 of NOTCH2 in the child and her father. In silico analysis considered the variant as likely deleterious. CRISPR/Cas9 was used to introduce the Notch24006G>C mutation into Notch2 to create Notch2em1Ecan mutant mice. Homozygous Notch2em1Ecan mutant mice were active, appeared healthy, had normal femoral length, but lower weights than controls. μCT of the distal femur revealed a 25 % decrease in trabecular bone volume, and a decrease in total, bone and marrow area, in periosteal perimeter and polar moment of inertia, revealing the presence of small and potentially fragile bones. Three-point bend testing demonstrated decreased toughness in Notch2em1Ecan femurs. Cancellous bone histomorphometry demonstrated decreased eroded surface, and Raman spectroscopy revealed normal mineral to matrix ratios, carbonate:phosphate and collagen peak ratios. A structure homology model of NOTCH2 EGF33-36 repeats suggests that the G1336R mutation may disrupt the local structure, reducing the flexibility of the extracellular domain and thereby affecting receptor activation and signaling. Indeed, there was a modest decrease in Notch canonical target genes in osteoblasts from Notch2em1Ecan mice. Osteoblast and osteoclast differentiation were diminished in cells from Notch2em1Ecan mice. In conclusion, a novel mutation affecting the NOTCH2 extracellular domain is associated with small and apparently fragile bones, possibly due to altered Notch signaling.

PURPOSE:An international working group (IWG) consisting of experts in X-linked hypophosphatemia (XLH) developed global guidelines providing a comprehensive, evidence-based approach to XLH diagnosis, management, and monitoring. METHODS:The IWG, consisting of 43 members as well as methodologists and a patient partner, conducted 2 systematic reviews (SRs) and narrative reviews to address key areas. The SRs addressed the impact of burosumab compared to conventional therapy (phosphate and active vitamin D) or no therapy on patient-important outcomes in adults. They also evaluated conventional therapy compared to no therapy. GRADE methodology was applied to evaluate the certainty of evidence. Non-GRADED recommendations were made in the presence of insufficient evidence to conduct SRs. These guidelines have been reviewed and endorsed by several medical and patient societies and organizations. RESULTS:The diagnosis of XLH is based on integrating clinical evaluation, laboratory findings confirming renal phosphate wasting (following exclusion of conditions mimicking XLH), and skeletal imaging. Fibroblast growth factor 23 measurement and DNA analysis are of value in the diagnosis, if available. Pathogenic or likely pathogenic variants in the PHEX gene are confirmatory but not necessary for the diagnosis. Management requires a multidisciplinary team knowledgeable and experienced in XLH. Effective medical therapy with burosumab can improve fracture and pseudofracture healing. MAIN CONCLUSION:In adults with XLH and fractures or pseudofractures, burosumab is recommended over no therapy (strong recommendation, GRADEd). Additionally, burosumab is suggested as the preferred treatment compared to conventional therapy (conditional recommendation, GRADEd) in the absence of fractures or pseudofractures. If burosumab is not available, symptomatic adults should be treated with conventional therapy (Non-GRADEd recommendation).

Fractures and pseudofractures cause considerable morbidity in adults with X-linked hypophosphatemia (XLH). They frequently occur in cortically-enriched bones of the lower extremities. Burosumab, a neutralizing antibody to FGF23, heals fractures in adults with XLH, presumably by healing osteomalacia. Histomorphometry has documented healing of osteomalacia in trabecular bone. The effects of burosumab on cortical bone have not been reported. Therefore, 3D-DXA measurements of the proximal femur were used to examine the impact of 1 yr of burosumab therapy on cortical and trabecular bone in symptomatic adults with XLH. Twenty volunteers from the registration trial for burosumab were separately consented for this study. DXA scans of the hip were obtained before and 6, 12, and 18-24 mo after drug therapy (1 mg/kg every 4 wk). 3D-DXA analyses were performed using 3D-Shaper software (3D-Shaper Medical). Changes in FN areal BMD (aBMD), TH aBMD, TH trabecular volumetric BMD (vBMD), FN trabecular vBMD, TH cortical surface BMD (sBMD), FN cortical sBMD, and FN cross-sectional moment of inertia (CSMI) were analyzed. Both TH and FN trabecular vBMD showed significant increases over the course of therapy (13.6% and 14.1% respectively at the end of treatment compared to baseline; p < .0001 for each). Fractures and pseudofractures often occur in the cortically-enriched FN in XLH. Burosumab induced a significant increase in FN cortical sBMD between 6 and 12 mo (p < .05) and between 6 and 18-24 mo of drug treatment (p < .05). The FN CSMI, an indicator of FN strength, also significantly increased at 12 and 18-24 mo when compared to baseline; p < .05 and p < .01, respectively. These data demonstrate that burosumab increases both cortical and trabecular bone in the hip, a site of frequent fracture in XLH.

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Background:Osteotomy and hemiepiphysiodesis are used to treat lower limb deformities in the rare musculoskeletal disease X-linked hypophosphatemia (XLH), but postsurgical complications and malalignment recurrence are possible. This retrospective analysis assessed whether treatment with burosumab, a fully human IgG1 monoclonal antibody to fibroblast growth factor 23 approved for treatment of rickets in XLH, improves lower limb malalignment toward age-specific normal values in children with XLH. Methods:Children with confirmed XLH received burosumab for 160 weeks in the open-label phase 2 study CL205, or conventional therapy (Pi/D) or burosumab for 64 weeks in the randomized, open-label phase 3 study CL301, with crossover from Pi/D to burosumab through 88 weeks. Full-length, anteroposterior lower limb radiographs were reviewed. The mechanical femoral-tibial angle (MFTA) of lower limbs was measured at baseline and postbaseline. Each MFTA was classified as normal (within 1 standard deviation [SD] of age-specific normal range) or clinically normal (within 2 degrees of normal). Results:Overall, 116 limbs were included (CL205, n = 26; CL301, n = 90). Varus or valgus limbs were observed at baseline in 21 (80.8%) limbs in CL205 and in 69 (76.7%) limbs in CL301. In CL205, mean (SD) MFTA decreased from 13.0° (6.7°) at baseline to 5.7° (6.0°) at week 64 and 1.0° (4.8°) at week 160. In CL301, mean (SD) MFTA decreased from 15.5° (13.6°) at baseline to 8.5° (10.0°) at week 64 in the burosumab arm, and in the crossover arm, from 9.2° (10.4°) at week 64 to 6.9° (9.4°) at week 88 (after 22 weeks of burosumab). The proportion of normal or clinically normal limbs increased with burosumab in CL205 (baseline to week 160, 19.2% to 58.3%) and in the CL301 burosumab arm (baseline to week 64, 19.6% to 37.0%) but not in the CL301 crossover arm (week 64-88, 34.1% to 33.3%). Conclusions:In children with XLH, long-term treatment with burosumab is capable of correcting the MFTA of varus and valgus lower limbs to a neutral alignment without requiring surgical intervention. Key Concepts:1.Treatment with burosumab led to the correction of lower limb angular deformity to neutral alignment in children with X-linked hypophosphatemia (XLH).2.Continued treatment with burosumab for at least 1 year appears to have further positive effects on the correction of lower limb angular deformity in children with XLH.3.Initial treatment with burosumab is indicated in young children with XLH for whom hemiepiphysiodesis is being considered. Level of Evidence:III.