Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia

X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients’ experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease. This Consensus Statement provides robust clinical evidence on the multidisciplinary management of children and adults with X-linked hypophosphataemia, with an emphasis on patients’ experiences and needs. It is the outcome of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.

diagnosis. XLH is a genetic disease characterized by rickets and osteomalacia and caused by pathogenic var iants in PHEX (which encodes phosphateregulating neutral endopeptidase PHEX) 2 . Owing to the variety of symptoms that can manifest, patients with XLH require the care of a large range of medical specialities, includ ing paediatricians, rheumatologists, endocrinologists, nephrologists, orthopaedic surgeons, neurologists, rehabilitation specialists and dentists, across the life course. All specialities are complementary, fulfilling an interdisciplinary patientcentred approach. In 2021, an international expert working group was convened by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) to discuss the features of this inter disciplinary management strategy to address patients' demands as well as unmet needs. The result of the working group discussions is this Consensus Statement, which provides the most current and robust clinical evidence on management of XLH.
After a brief review of the normal mineraliza tion process and the key components involved, this Consensus Statement covers the clinical manifestations of phosphate depletion, the evaluation of a patient with hypophosphataemia and the diagnostic workup that leads to the diagnosis of hypophosphataemia related to FGF23 excess. The Consensus Statement is centred on XLH and its main differential diagnoses in terms of clinical manifestations, as well as management via a multidisciplinary approach.
Since the last clinical practice recommendations for XLH that were released in 2019 (ref. 3 ), several original studies have been published that cover the clinical mani festations of the disease and describe the clinical efficacy of the antiFGF23 monoclonal antibody burosumab in treating this condition, including patientreported out comes. This more robust evidence base now permits, in this Consensus Statement, revised and updated clinical recommendations on the use of this novel agent in the treatment of XLH.

Methodology
This Consensus Statement provides the consen sus of an expert working group of ESCEO in Geneva (Switzerland), under the auspices of the WHO Collaborating Centre for Public Health Aspects of Musculoskeletal Health and Aging (Liège, Belgium). The group comprised a diverse panel of 25 expert clinicians from 14 countries chosen for their expertise and publi cation record in XLH and related disorders, including orthopaedic surgeons, physical and rehabilitation medi cine specialists, rheumatologists, endocrinologists, nephrologists, paediatricians, geriatricians, clinical bio chemists and clinical pharmacologists. The group also included two patients with XLH and one relative.
In advance of the first hybrid inperson-virtual meet ing on 5 February 2021, experts were assigned specific topics on which they conducted extensive narrative liter ature reviews. Topics considered by the group included: pathophysiology of phosphate wasting syndromes; labo ratory assessment; burden of XLH disease; management of phosphate wasting syndromes in children and ado lescents; management of phosphate wasting syndromes in adults; management of TIO; and the role of dentists and orthopaedic surgeons in the management of patients with phosphate wasting syndromes. At the meeting, the experts presented the results of these reviews, together with draft recommendations, to the wider group, which included patient representatives. During the discussion, the 2019 EvidenceBased Guideline 3 was updated with the literature released since its publication. Discussions were held and experts deliberated on the quality, scope and context of the collected evidence, and the recom mendations made. Further evidence was incorporated as suggested by members at the meeting. Agreement on statements and recommendations between all coauthors, including the patients, was obtained after extensive discussions, and during critical iterative revisions of the manuscript drafts, leading to consen sus on all items. We did not grade the strength of the recommendations.
An executive writing group (A.T., R.R.) was appointed to undertake preparation of the first draft of the manu script based on draft recommendations as agreed by all participants at the meeting. This draft manuscript was then circulated to all the members of the expert group, and patient representatives, for critical revision. Any additionally identified highquality evidence published following the expert group meeting was subsequently incorporated by the executive writing group. The first author coordinated the preparation of the final ver sion of the manuscript, which was circulated to the entire expert group for final approval of the content and of the contained recommendations, which had been provisionally approved unanimously at the group meeting. Following the unanimous final endorsement of the recom mendations and content by all members of the expert group, the Consensus Statement was submitted for publication. The patient representatives were invited to provide their comments at all steps of the discussions.

Physiology of bone mineralization
Phosphate is involved in a wide variety of essential cel lular functions 4 . For example, phosphate is a constitu ent of molecules such as ATP, as well as nucleotides in DNA and RNA. Furthermore, phosphate contributes to intracellular signalling molecules, such as cAMP and membranous glycerophospholipids, and signal trans duction pathways. Phosphate has an important role as an extracellular fluid (ECF) buffer in blood and urine. Importantly, phosphate is a major constituent of bone and teeth in the form of calcium phosphate crystals (hydroxyapatite) 5 .
Intestinal absorption of phosphate occurs by passive paracellular and active transcellular vitamin Ddependent mechanisms, with 1,25dihydroxy vitamin D (1,25 (OH) 2 D or calcitriol) enhancing the expression of sodiumdependent phosphate transport protein 2B 6 . Renal tubular phosphate reabsorption adapts blood con centrations of phosphate to the needs of the organism in relation to growth, and cartilage and bone mineraliza tion. Indeed, the kidney is able to regulate the maximal reabsorptive capacity, which is expressed as the ratio of maximal TRP to glomerular filtration rate (TmPi/ GFR) in the proximal tubule in response to variations in dietary phosphate intake. Concentrations of phos phate in ECF and phosphate homeostasis are regulated by serum PTH along with other mechanisms, with a central role played by FGF23 (refs 7,8 ). Secreted by osteo cytes and osteoblasts, FGF23 increases renal phos phate excretion by downregulating the expression of sodiumdependent phosphate transport protein 2A and sodiumdependent phosphate transport protein 2C, and triggering their internalization and degradation in the apical brush border membrane of the proximal tubule 7,9,10 . FGF23 also directly decreases renal proxi mal tubule production of 1,25(OH) 2 D, by suppressing the expression of 25OHD1 αhydroxylase (encoded by CYP27B1). By increasing expression of vitamin D 3 24hydroxylase, FGF23 also catabolizes 25hydroxy vitamin D (25(OH)D or calcifediol) and 1,25(OH) 2 D into inactive forms 11 , which leads to reduced intestinal phosphate and calcium absorption 12 .
The maintenance of a normal concentration of phos phate in ECF is important for hydroxyapatite crystal formation and the mineralization process. With chronic hypophosphataemia, phosphate availability at the min eralization front is reduced. This deficit is responsible for the development of rickets in children and adoles cents, and osteomalacia in adults. Whether 1,25(OH) 2 D has a role in mineralization that is independent of its effect on intestinal mineral absorption is a matter of debate. Indeed, in experimental models of severely vita min Ddeficient rats, infusion of calcium and phosphate without vitamin D permitted bone growth, cartilage and osteoid mineralization similar to that observed with vitamin D administration alone. This finding supports the view that vitamin D exerts an indirect effect on bone mineralization through maintenance of normal serum levels of calcium and phosphate 13,14 . Other experimen tal studies in vitamin D receptornull mice and in mice with mutations in Cyp27b1 (ref. 15 ) showed that provi sion of sufficient amounts of calcium and phosphate rescues the rickets phenotype 16 . Hypophosphataemia leads to rickets by impairing caspasemediated apopto sis of hypertrophic chondrocytes 17 . On the other hand, 1,25(OH) 2 D might directly promote osteoblast differ entiation and production of matrix vesicles in vitro, thereby enabling mineralization 18,19 . Moreover, numer ous proteins that promote mineralization are regulated by 1,25(OH) 2 D (ref. 19 ). A 2020 clinical case report described an infant girl with concomitant hypophos phatasia and vitamin Ddeficiency rickets despite nor mal serum values of calcium and phosphate, which was treated by cholecalciferol (vitamin D 3 ) administration 20 , consistent with a direct effect of vitamin D on the mineralization process.

Manifestations of phosphate depletion
Disorders with hypophosphataemia have a variety of manifestations that depend upon the underlying pathophysiological mechanism as well as the severity and the duration of phosphate depletion, and whether hypophosphataemia presents during the growth period or in adulthood 1 . Intracellular phosphate depletion leads to a decrease in red blood cell 2,3diphosphoglycerate and ATP concentrations; the latter has multiple cellular functions in the central nervous system and in skeletal and smooth muscle cells, and decreased ATP levels in skeletal muscle possibly contribute to proximal myopathy that has been described in hypophosphataemia 21 . Severe hypophosphataemia can be associated with neuro muscular symptoms and altered cardiac or respiratory function, even though only weak evidence demonstrates a causal relationship 1 . In hypophosphataemia, the changes that occur at the growth plate and mineraliza tion defects contribute to the skeletal deformities and growth alterations that are the dominant clinical mani festations in childhood. The clinical features of genetic forms of hypophosphataemia manifesting in early life are listed in Box 1. Of note, osteomalacia, which mani fests in adults with hypophosphataemia, is a risk factor for pseudofractures 2 .
Evaluating patients with hypophosphataemia Ageadjusted references of phosphate values need to be considered when evaluating patients with suspected hypophosphataemia. In addition, serum levels of phos phate exhibit a circadian rhythm, with a peak at around 3.00 a.m. and a nadir at around 11.00 a.m. 22 . In some rare cases, phosphate assay interference can occur due to the presence of monoclonal immunoglobulin 23 , med ications (such as highdose liposomal amphotericin B, niacin or excessive use of phosphate binders) 24 or hyperbilirubinaemia 25 , which can result in pseudohy pophosphataemia. This interference should be ruled out before any further evaluation.
In children, the maximal TRP can be calculated from fasting blood and urine samples using the formula: TmPi/ GFR = plasma phosphate concentration − ((urinary phosphate concentration × plasma creatinine concen tration)/urinary creatinine concentration) 26,27 . Alth ough nonfasting specimens can be sampled, a fasting state usually implies a morning sample collection, ensuring some consistency in the measurements dur ing the phosphate circadian rhythm. An appropriate reference range according to the formula used should be applied.
To evaluate renal tubular phosphate reabsorp tion in adults, TmPi/GFR is calculated from fasting paired plasma and second morning void urine samples (obtained 2 h after the first void urine) for phosphate and creatinine measurement 28 . This parameter can be obtained using the nomogram of Walton and Bijvoet 28 or using the algorithm of Kenny and Glen 29 . According to Kenny and Glen, if fractional TRP is less than or equal to 0.86, then TmPi/GFR = TRP × serum phosphate con centration. By contrast, if TRP is greater than 0.86, then TmPi/GFR = α × serum phosphate concentration, where α = 0.3 × TRP/(1 − (0.8 × TRP)). The ratio of maximal TRP to GFR varies with age, and higher values are seen during the accelerated growth period in children than are seen in adults 30 . Normal values of TmPi/GFR range from 0.8 to 1.35 mmol/l GFR in adults.
Once renal phosphate wasting is demonstrated in children or adults, four important regulating hormones of phosphate metabolism should be evaluated; these are: FGF23, PTH (both phosphaturic factors), 25(OH)D and 1,25(OH) 2 D, which is the active form of vita min D. After skin synthesis of vitamin D or ingestion of vitamin Dcontaining foods or supplements, vita min D is hydroxylated in the liver to produce 25(OH)D, which is the most abundant vitamin D metabolite. 25(OH)D has a halflife of several weeks and its blood concentration reflects vitamin D status of the individ ual. A second hydroxylation event occurs on 25(OH)D in the kidneys by 25OHD1 αhydroxylase to produce 1,25(OH) 2 D. This second hydroxylation is tightly regu lated by variations in the circulating levels of PTH and ECF concentrations of calcium or phosphate. Serum concentrations of 1,25(OH) 2 D can be normal even in individuals with severe vitamin D deficiency. The halflife of 1,25(OH) 2 D is between 5 and 8 h, depend ing on the method used to assess it and the study [31][32][33] . In the past, 1,25(OH) 2 D was measured by poorly specific radioimmunoassays. Over the past 10 years, automated immunoassays and liquid chromatography tandem mass spectrometry methods have become available, and these offer improved specificity 34 ; however, precision errors remain high according to the Vitamin D External Quality Assessment Scheme external control. Furthermore, no standard reference calibrator nor reference method exists for 1,25(OH) 2 D measurement 35 . As is the case for serum levels of phos phate, 1,25(OH) 2 D levels also vary with age. Values are highest during the first three years of life and then decrease, remaining stable thereafter 36,37 . Agespecific reference intervals should thus be used. A low or inap propriately normal plasma level of calcitriol in the presence of hypophosphataemia might be suggestive of FGF23 excess.
FGF23 is an endocrine member of the family of fibroblast growth factors and is primarily produced by osteocytes and osteoblasts 38 . FGF23 is a protein with 251 amino acids; however, a 24amino acid signal peptide is removed before secretion and the mature secreted FGF23 protein is approximately 32 kDa 39 . The pro duction of FGF23 is mainly stimulated by 1,25(OH) 2 D and a high phosphate diet 40,41 . Many other factors are known to affect FGF23 production, such as PTH, cal cium and inflammation. However, the balance between production and degradation by cleavage of the mature FGF23 protein is maintained during inflammation 42  the carboxy terminus between amino acids 179 and 180 (ref. 44 ). Of note, mutations that cause loss of function of PHEX result in increased circulating levels of FGF23 and this increase explains many but not all XLHassociated complications 45 .
FGF23 assays can either detect the intact (fulllength) and biologically active form of mature 227amino acid FGF23, or both the intact protein and Cterminal frag ments that result from cleavage. The antibodies used in the assays recognize epitopes within the aminoterminal and Cterminal domains, which flank the cleavage point, or they recognize only the epitopes within the Cterminal portion. These FGF23 assays are generally considered as reliable 46 . Nine assays recognizing only the 'intact' form are commercially available: seven manual enzymelinked immunosorbent assays (ELISA) and two automated chemiluminescent assays 47,48 . In addition, three ELISAs that recognize both the intact form and the Cterminal fragments (generally called 'Cterminal' assays) are available. Most of these FGF23 assays are for research use only. The various FGF23 assays are described in Supplementary Table 1 (ref. 49 ). The units used for the results of all FGF23 assays differ between the Cterminal (relative units, RU, per millilitre) and the intact methods (picograms per millilitre or picomoles per millilitre). No synthetic or purified natural FGF23 is available for use as a standard method nor a reference method. Of note, FGF23 is more stable in EDTA plasma (plasma with an excess of a powerful chelating agent) than in serum at room temperature. Furthermore, FGF23 values obtained in EDTA plasma are also higher than those obtained in serum 47,50 . Nevertheless, whether plasma or serum should be used for FGF23 assessment is very assayspecific. Although some assays can be accurate with either plasma or serum, best prac tice is to use the sample type recommended by the manufacturer.
For initial diagnostic purposes, fasting phosphate and FGF23 plasma samples should be collected 1 to 2 weeks after phosphate and calcitriol discontinuation, if the patient under evaluation is already receiving some treatment. Interestingly, the 2018 approved treatment for XLH (the monoclonal antibody against FGF23, burosumab) can interfere with the FGF23 assay 51 47 . Of note, individuals older than 60 years and men have slightly higher blood concentra tions of FGF23 than younger individuals and women 47 . For paediatric use, agedependent and sexdependent reference range data have been published with the Cterminal FGF23 assay of Immutopics 52 . However, intact FGF23 measurements are probably more reliable for the diagnosis of FGF23mediated hypophos phataemia, as they can reveal inappropriately normal levels of intact FGF23, such as those seen in XLH or TIO 48,53 .
Once elevated or inappropriately normal blood levels of FGF23 are demonstrated in a patient with hypophos phataemia, different possible causes can be consid ered. Genetic causes of FGF23-mediated hypophosphataemia XLH is due to a lossoffunction pathogenic variant in PHEX, which is located on Xp22.11. PHEX is a mem brane protein expressed in bone and teeth tissues 54 . The precise mechanism by which PHEX mutations lead to FGF23 gene overexpression and/or its decreased catab olism is unknown. With an incidence estimated at 3.9 affected individuals per 100,000 live births 55,56 , XLH is the most frequent cause of hypophosphataemic rick ets of genetic origin (80% of individuals with genetic phosphate wasting syndromes have XLH). The UK prevalence is estimated to be 1.5 patients per 100,000 children and 1.6 patients per 100,000 adults, with an excess mortality 57 . By contrast, in Norway, XLH preva lence is 1.7 patients per 100,000 children 58 and in south ern Denmark prevalence is 4.8 patients per 100,000 children 55 . Such variation in the prevalence (which ranges from 1 in 20,000 to 1 in 60,000) of the disease could be related to selection bias or different genetic backgrounds across populations. A second inherited form of hypophosphatae mia related to FGF23 excess is autosomal dominant hypophosphataemic rickets (ADHR). This condition is caused by pathogenic variants at the cleavage site of FGF23, which precisely target Arg179 and Ser180, thus inducing a resistance to proteolytic degradation in FGF23 (ref. 59 ). The clinical and biochemical phenotype of ADHR seem particularly sensitive to iron deficiency. In normal individuals, iron deficiency stimulates FGF23 transcription but also increases FGF23 cleavage, which results in normal circulating levels of intact FGF23 (ref. 60 ). In ADHR, iron deficiency stimulates production of FGF23 as usual, but it is not efficiently cleaved and thus becomes elevated 61,62 .
Autosomal recessive hypophosphataemic rickets (ARHR) exists in three forms. First, ARHR type 1 is caused by biallelic variants in DMP1, which encodes an extracellular matrix protein that is important for proper mineralization of bone and dentin 63 . Second, ARHR type 2 is caused by biallelic variants in ENPP1 (ref. 64 ), which encodes an enzyme involved in the  generation of pyrophosphate. Biallelic pathogenic var iants in ENPP1 lead to generalized arterial calcification of infancy (GACI). Children who survive GACI can go on to develop ARHR type 2 (ref. 65 ). In one series of 247 adults and children with GACI, 11 initially presented with ARHR type 2. All had ENNP1 pathogenic vari ants and seven had evidence of ectopic calcifications 66 . Third, ARHR type 3 is associated with biallelic patho genic variants that inactivate FAM20C (which encodes a secreted protein kinase that induces posttranslational modification of FGF23 and enhances the processing of FGF23 protein), preventing FGF23 degradation 67 . Of note, a de novo translocation adjacent to KL (which encodes αklotho) between chromosomes 9 and 13 has been described, which results in elevated circulating levels of αklotho and FGF23 (ref. 68 ). The disorder fea tured hypophosphataemic rickets and severe hyperpara thyroidism, with a phenotype characterized by specific facial features and skull anomalies.

Diagnosis of genetic causes of FGF23-mediated hypophosphataemia: recommendations.
• In addition to the main biochemical features, the diagnosis of XLH is based on the clinical evidence of rickets, radiographic signs and when possible, a positive family history (which is seen in 50-70% of patients) with a dominant transmission 69,70 . • Given the difficulties in the differentiation of the multiple possible diagnoses, and given also that the antiFGF23 antibody, burosumab, is only approved for use in XLH (and in TIO in certain coun tries), the diagnosis of XLH should be confirmed by genetic analysis of PHEX in children and adults. Tumour-induced osteomalacia. TIO is a rare acquired disorder mediated by FGF23 that is produced by often benign mesenchymal tumours. This condition has also been observed in several cancers (for example, prostate and breast) 75,76 . The biochemical features of TIO are similar to those of XLH, with hypophosphataemia, low TmPi/GFR, low or inappropriately normal circulating levels of 1,25(OH) 2 D, and high or inappropriately nor mal circulating levels of FGF23 (ref. 77 ). However, clinical features such as dental complications, enthesopathy or osteoarthritis are less commonly found in TIO than in XLH. This difference might be due to the development of the disorder during adulthood and/or a short dis ease duration 78 . Although XLH can be associated with increased BMD in certain patients, BMD is typically low in TIO 79 , with an important deterioration in bone microarchitecture 80 . The tumours in TIO are usually small, with slow growth and can be located anywhere in the body. Once the diagnosis is established, identify ing the location of the tumour might be difficult despite a multitude of sophisticated imaging modalities currently available (for example, PET-CT with 68 GaDOTATATE or fluorodeoxyglucose). These examinations can be fol lowed up with targeted venous sampling to determine if suspect lesions found on imaging are secreting FGF23 (ref. 81 ). Effort should be made to find the tumour, with repeated scans at annual or 2year intervals, as complete surgical tumour resection is curative and leads to a spec tacular clinical improvement and increases in BMD 79 . When tumour resection is not possible, due to an inabil ity to locate or access the tumour, medical treatment and management are similar to those in XLH. Among new therapeutic procedures, imageguided tumour ablation 82 and the antiFGF23 monoclonal antibody burosumab have shown promising results 83 .

Diversity of XLH clinical manifestations
XLH has clinical manifestations that affect many differ ent organs and tissues. Box 2 summarizes pathophysi ological changes and clinical implications by organ in XLH. In a 2019 survey that involved 232 adults and 90 children with XLH 84 , bowing of the femur was reported in 63% and bowing of the tibia was reported in 72% of children. A similar prevalence was found in adults.
Of note, 47% of children and 94% of adults reported sur gical interventions, most commonly osteotomy, followed by epiphysiodesis. History of fracture or pseudofractures was reported in 44% of adults. In a metaanalysis, 18% to 52% of adult patients with XLH experienced fractures or pseudofractures 85 . Despite conventional treatment with phosphate supplements and vitamin D metabolites dur ing childhood, 57% reported a history of orthopaedic surgery. Another study showed an unexpected reduction in survival in adult patients with XLH 57 .
In some children with XLH, craniosynostosis results from premature fusion of the cranial sutures during growth 86,87 . The pathophysiology of this complication has not been fully elucidated but might involve an upreg ulation of FGF receptor 2 (FGFR2) or FGFR3 signalling and crossbinding of FGF23 with FGFR2 and FGFR3, which affects intramembranous and endochondral ossi fication of the skull 88 . Patients with XLH can also have a disproportionately short stature 3 , which does not cor rect even with treatment from birth onwards and despite correction of leg deformities.
Besides the clinical and radiological evidence of rick ets that is present in a large proportion of patients with XLH, muscle weakness has been reported in 30% of chil dren and 60% of adults 84 . Compared to an agematched and sexmatched population, affected individuals dis play normal muscle volume, but a lower muscle density and lower muscle strength and power 89 . The reasons for muscle weakness are unknown and might be linked with hypophosphataemia and deficient energy delivery to the muscle by decreased muscle ATP synthesis, as well as with limb deformities and deconditioning. This manifestation will require further efforts to be completely understood 90 .
Early osteoarthritis and enthesopathy (calcifica tion of the tendons and ligaments in close proximity to bone) can limit the mobility of patients with XLH and cause pain. In one study in adult patients with XLH (aged >30 years), 80% of patients had early osteoar thritis and 100% of patients had enthesopathy 91 , which explains the high proportion of individuals with XLH who live with pain. Enthesopathy and spinal stenosis are common (affecting 27% and 19% of adults with XLH, respectively), as are dental abscesses, which affect 51% of children and 82% of adults with XLH. Nearly all adults with XLH experienced pain in another study 84 .

Box 2 | Pathophysiological changes and clinical implications by organ in X-linked hypophosphataemia Bone
Pathophysiological changes • Impaired mineralization: increased unmineralized osteoid due to hypophosphataemia • Decreased calcitriol production (including locally) • local suppression of tissue non-specific alkaline phosphatase (TnAP) • Accumulation of osteopontin and aspartic acid-rich motif peptide (pASARm)  The mechanism of enthesophyte development is poorly understood and might result from a direct effect of FGF23 (refs 92,93 ). Conventional therapy does not nota bly influence enthesopathy 94,95 . The bowing of the long bones might potentially increase strain on the entheses. The mechanisms underlying early osteoarthritis devel opment are not completely understood and cannot be fully explained by abnormal mechanical loading due to skeletal deformities. However, the mechanisms through which increased FGF23 might interfere with cartilage development require further investigation 96 .
Among extraskeletal manifestations, neurologi cal manifestations also occur due to spinal stenosis or type I Chiari malformation (defined as brain tissue that extends into the cervical spinal canal) 97 . Clinically important spinal canal stenosis and spinal cord or nerve compression are the consequence of ossification of the posterior longitudinal ligament in conjunction with hypertrophy of the facet joints, thickening of the laminae and calcification of the ligamenta flava 98,99 . Of note, hear ing loss has been reported in 16% to 76% of individuals with XLH 2,100-102 . However, the mechanism is unclear 103 .
Nephrocalcinosis has not been reported in untreated patients with XLH but is considered an adverse effect of conventional treatment (particularly phosphate sup plements) and occurs through treatmentrelated devel opment of hypercalciuria, hyperphosphaturia and/or secondary hyperparathyroidism 104 . FGF23 has also been suggested to enhance renal calcium reabsorption via the transient receptor potential cation channel subfamily V member 5 (TRPV5) channel in the distal tubule, which could potentially promote cellular calcium accumulation and calcification, as does PTH [105][106][107] . The frequency of nephrocalcinosis is highly variable and ranges from 30% to 70% in patients with XLH 3 . Nephrocalcinosis might be associated with hypertension and left ventricular hypertrophy 105 . In patients with XLH, FGF23 might also have a direct effect on cardiomyocytes and vessels, as is seen in chronic renal failure; however, circulating levels of FGF23 in XLH are well below those encountered in renal failure, making a myocardial direct toxic effect less likely 108 .
Some limited data exist supporting the view that patients with XLH might be prone to develop earlyonset hypertension and display a higher prevalence of hyper tension as compared with the general population. For example, 27% of adult patients with XLH were found to be affected by hypertension in a previous study 105 . In patients with XLH, hypertension seems to be associ ated with the presence of secondary or tertiary hyper parathyroidism, nephrocalcinosis and/or reduced GFR 109 . FGF23induced renal sodium reabsorption could have a role in this phenomenon 106 . Children and adults with XLH also have a high prevalence of obesity, partly due to impaired mobility in relation to chronic bone complications 102,110 . Obesity substantially reduces gait quality in children with XLH 111 . In addition, some patients with XLH also experience glycosuria, which could confuse the clinical diagnosis and might lead clin icians to suspect a Fanconitype syndrome rather than FGF23mediated hypophosphataemia [112][113][114][115] .
Of note, the earlier that appropriate treatment is initi ated in childhood, the lower the severity of clinical symp toms and consequences observed in adulthood [116][117][118] . Moreover, adults with XLH display specific symptoms related to early development of osteoarthritis, osteoma lacia with pseudofractures, impaired muscle function, chronic bone and joint pain, stiffness, impaired mobil ity and disability, depression 119 and early susceptibility to dental abscesses. All these manifestations negatively affect the patient's quality of life 120 (Box 3; figs 1,2).

Management of XLH
Conventional treatment. During growth, conventional treatment with phosphate supplements and active vita min D metabolites can be offered to all children with XLH, as soon as the diagnosis is established. The dose should be adapted to the severity of the phenotype, with starting doses ranging from 20 mg/kg to 60 mg/kg body weight per day (0.7-2.0 mmol/kg) of elemental phosphate 2 in four to six divided doses. Calcitriol should be given at a starting dose of 20-30 ng/kg body weight per day in one or two doses. Owing to a longer halflife than calcitriol, alfacalcidol can be given once daily at an initial dose of 30-50 ng/kg per day. A more aggressive approach has been suggested that uses high calcitriol doses of up to 40 ng/kg per day 2 , or even shortterm higher doses as a loading dose, which might help in pre venting hyperparathyroidism but could also result in

Box 3 | Living with XLH -burden of XLH disease and symptoms that affect quality of life
• Pain, particularly in and along the tibia, and in joints (for example, the ankles, knees and hips). -Significant limitations on daily physical activities including sports and exercise, walking and standing for long periods of time. Also results in social effects, especially at school age (for example, unable to join friends or other students in sporting events and physical activities). -leisure activity limitations • Physical deformities such as bowing of the legs, short stature or misshapen head.
-Physical deformities have major emotional and psychological consequences, from childhood through to adolescence and even into adulthood. They can lead to low self-esteem, depression, isolation and social life limitation. Patients who require complex deformity correction will undergo a lengthy rehabilitation process. The burden of recovery (an inability to walk and being wheelchair-bound), combined with dependency on medication (opiates such as oxycodone) and loss of freedom and mobility has major emotional and mental effects, which should not be underestimated when planning and during recovery from corrective surgery.
an increased risk of nephrocalcinosis 121 . Less frequent dosing with phosphate or vitamin D metabolites can be considered when serum levels of alkaline phosphatase (ALP) are in the normal range, in order to improve adherence in adolescents. Of note, reference ranges for ALP are both agespecific and sexspecific. Vitamin D deficiency should also be corrected to prevent the devel opment of secondary hyperparathyroidism, which can worsen renal phosphate wasting. In children, the clinical efficacy of conventional treat ment is well established, in terms of improved growth and reduced severity of leg deformities, decreased occur rence of dental complications and pain control [122][123][124][125][126][127][128] . As serum phosphate is measured under fasting conditions and given the short halflife of phosphate supplements (serum levels of phosphate return to baseline concen trations within 1.5 h after intake 129 ), fasting phosphate values might be lower than in a postabsorptive state. Thus, conventional treatment usually fails to normalize serum levels of phosphate, and to target the normaliza tion of serum levels of phosphate is not a suitable goal. The goal of treatment is to prevent or cure rickets 2,116 . Importantly, overtreating with phosphate supplements should be avoided owing to the risk of nephrocalcinosis and of secondary hyperparathyroidism.
In adults, the considerable variety of phenotypes of XLH can substantially influence the appropriate treatment. Furthermore, the condition is rarely misdi agnosed as ankylosing spondylitis, early osteoarthritis or Forestier disease. In 2021, a middleaged man was reported as being misdiagnosed with achondroplasia all through childhood and adulthood owing to his short stature and deformed extremities 130 .
Longterm treatment with phosphate supplements 131 and decreased production of calcitriol by FGF23 excess contribute to the development of hyperparathyroidism. Adults with XLH are particularly prone to developing secondary and eventually tertiary hyperparathyroidism with hypercalcaemia, which affected 25% and 10% of patients with XLH respectively, in one study 132 . If availa ble, paricalcitol could be added to conventional therapy for PTH suppression. Paricalcitol was tested in a ran domized trial in patients with XLH without prevalent hypercalcaemia 133 . Tertiary hyperparathyroidism should primarily be treated by parathyroid surgery 132 . If there are contraindications to surgery or if the patient declines this intervention, the calcimimetic cinacalcet could be considered 134,135 .
The continuation of conventional treatment in adults is still debated. In a cohort of 52 adults with XLH, con tinuation of conventional treatment during adulthood tended to prevent dental abscess 136 , and to reduce per iodontitis frequency and severity 137 . However, conven tional treatment in adults does not seem to affect the course of enthesopathy 136 . By contrast, in Hyp mice (a model of human XLH), conventional treatment did not improve enthesopathy 95 or exacerbated the miner alization of enthesis 138 . Neither hearing loss nor osteoar thritis seem to be influenced by conventional treatment 3 . Evidence, mostly obtained from case reports, suggests the efficacy of conventional treatment on bone pain related to osteomalacia, pseudofractures and fracture healing 2,139 . However, robust evidence that asympto matic adults should be treated is still missing. Transient treatment regimens can be considered in those under going orthopaedic or dental surgery to promote bone mineralization and the healing process. If so, treatment should be started before and continued 3-6 months after the surgical intervention 2 . When growth is completed, the dose of oral phosphate must be progressively decreased down to the lowest dose consistent with relief of symp toms. The doses of alfacalcidol or calcitriol should be adjusted to the required dose of phosphate to ensure normal mineral metabolism, as reflected by normal  serum levels of ALP, PTH and calcium, without signs of nephrocalcinosis. In some instances, lowdose active vitamin D analogues might be sufficient to achieve nor mal mineral metabolism and symptom relief without additional phosphate supplements.
During pregnancy, the need for phosphate increases, particularly during the third trimester, with an active maternal-fetal transport by the placenta. For those patients not receiving any treatment before pregnancy, conventional treatment could be considered and con tinued until the end of breastfeeding. Neonates born from mothers with XLH do not display skeletal abnor malities at birth 91 but preliminary findings suggest that they might have a birthweight slightly lower than normal (A. Linglart, unpublished work). In summary, we suggest that clinicians consider monitoring mineral metabolism in pregnant and lactating women and administering conventional XLH treatment if needed. Genetic testing of PHEX should be performed in the newborn baby. Given the time needed to get the results of such testing, we recommend screening the newborn baby at 7 days and, if the first survey is normal, 1 month after birth with the following parameters: plasma creatinine, ALP, PTH, 25OHD and phosphate, and urinary phosphate and cre atinine. These parameters can be used to calculate the TmPi/GFR, as this ratio and the serum levels of phos phate might remain in the lower normal range during the first months of life. Genetic testing is not absolutely necessary when there is a wellknown family history and biochemical findings consistent with XLH. Also, in some settings, genetic testing is not available or is pro hibitively expensive. Conversely, targeted genetic testing can be done fairly rapidly and inexpensively when the pathogenic variant in the relative is already known.

Adverse effects of conventional treatment.
Adverse effects of conventional treatment include intestinal discomfort due to phosphate supplements, with nausea, diarrhoea, hypercalciuria and nephrocalcinosis reported in 30% to 70% of patients 3 . Excessive oral phosphate intake might also promote nephrocalcinosis 140 . Secondary and tertiary hyperparathyroidism due to longstanding stimulation The patient had important varus deformities of the tibias and underwent corrective surgical procedures: the first operation was a bilateral tibial osteotomy at age 20 years and a second operation was performed on the right side at age 22 years. The osteotomy site on the right fibula did not consolidate until the age of 25. a | At the age of 43 years, in the context of diffuse pain, X-ray evaluation showed multiple pseudofractures located on the left femur, and right and left tibias, with important deformations. b | Conventional treatment was started, which was associated with rapid improvement in the pain and progressive healing of the pseudofractures. c | At the age of 48 years, he developed symptomatic spinal cord compression at the level of thoracic vertebra 7 and thoracic vertebra 8 due to enthesopathy affecting the ligamentum flavum. He underwent a posterior decompression at the levels of compression sites (arrows indicate compression). of parathyroid glands by phosphate supplements and further suppression of 1,25(OH) 2 D production by FGF23 might also be seen in patients with XLH 141 . Rehabilitation. Specific programmes of regular physi cal exercises and physiotherapy should be followed by individuals with XLH to prevent or improve muscle weak ness, back pain, joint pain and stiffness, and to increase mobility 143 . Physiotherapy should promote muscle strength, improve balance, joint motion and general mobility, by resistance exercise training in combination with other muscle function therapy 3 . Leisure sport activ ities are recommended. Specific and tailored programme rehabilitation is often necessary after orthopaedic surgery and in those with enthesopathy or osteoarthritis 3 .

Burosumab treatment in children.
Conventional treat ment counteracts two consequences of high circulating levels of FGF23, which are hypophosphataemia and low circulating levels of 1,25(OH) 2 D; however, conventional treatment does not fully correct the XLH phenotype due to the PHEX pathogenic variant. Furthermore, conven tional therapy increases the circulating levels of FGF23 and PTH, potentially exacerbating hypophosphatae mia. Thus, a logical treatment approach is to use buro sumab, a recombinant, monoclonal IgG antibody against FGF23. It is recommended that healthcare providers consider burosumab treatment in children with XLH aged 1 year or older (or from 6 months, as approved in some countries, such as the USA) and in adolescents with radiographic evidence of bone disease. The indi cations that were recommended in the 2019 guidelines 3 are overt bone disease (active rickets on plain radiog raphy) and disease that is refractory to conventional therapy, the presence of associated complica tions such as pseudofractures and an inability to adhere to conventional treatment. The superiority of burosumab over conventional treatment has been shown in terms of serum phos phate control 144,145 , healing of rachitic bone and/or of mineralization defects, improvements in bowing of legs, improved physical ability (as measured by walking distance in the 6min walking test) and pain control. Burosumab can also be considered as firstline therapy in children with XLH. Of note, patients included in the comparative trial were severely affected and might not have represented the full spectrum of disease severity encountered in daily practice. In addition, patients with secondary hyperparathyroidism were excluded. The effect of burosumab on longitudinal growth in children during treatment periods of up to 64 weeks was rather small (about +0.2 s.d. score), which suggests the existence of additional pathogenic factors; for example, a PHEX mutationrelated osteoblast defect that impairs growth in children with XLH 145 . Whether burosumab confers advantages in mildly affected individuals remains to be seen. Longterm studies are also needed to evaluate the effect of this therapy on the clinical burden of XLH, such as bone deformities, dental complications and the num ber of surgical interventions. Thus, in children with mild disease who are easily managed with conventional ther apy, treatment with burosumab is probably not warranted because of the large annual cost of the drug (around US $200,000). In this population, a trial of conventional therapy is indicated rather than considering burosumab as firstline therapy at present. As all the studies evalu ated children aged 1-12 years 144,145 , in some countries, the use of burosumab is limited to children in this age range. We consider this position highly questionable and recommend continuing treatment until end of growth.
The starting dose of burosumab in children with XLH is 0.8 mg/kg every 2 weeks subcutaneously, and this dose is adjusted to bring fasting serum levels of phos phate within the lower end of the normal reference range for age (maximum dose 2 mg/kg per 14 days or 90 mg per 14 days). As the peak serum concentration of buro sumab is reached by 7 to 11 days after injection, serum levels of phosphate should ideally be measured during that period to determine whether the treatment is caus ing hyperphosphataemia and between days 12 and 14 to demonstrate treatment efficacy 3 . The level that serum phosphate should increase to influence bone healing is currently unclear. • Consider burosumab treatment as firstline therapy in children with XLH aged 1 year or older (6 months in some countries, such as the USA), and in adoles cents with radiographic evidence of severe bone disease. • In children with mild disease, a trial of conventional therapy is suggested rather than considering buro sumab as a firstline therapy. • Once started, treatment with burosumab should be continued until the closure of the growth plate. A multidisciplinary evaluation should be conducted with the adult team to consider the followup of burosumab through adulthood.

Burosumab treatment in adults.
In adults with XLH, when burosumab was administered subcutaneously every 4 weeks at a starting dose of 1 mg/kg rounded to the nearest 10 mg, the treatment was shown to nor malize the serum levels of phosphate to above the lower limit of the normal range in most patients stud ied. Clinically, the Western Ontario and McMaster Universities Arthritis Index stiffness subscale score was improved, as was the Worst Pain Score and Physi cal Function subscore of the SF36 quality of life questionnaire [146][147][148][149][150] . In a randomized doubleblind placebocontrolled study, burosumab treatment in adults with XLH resulted in improved fracture heal ing (overt fractures and pseudofractures) at week 24 compared with placebo, and this improvement contin ued up to 48 weeks 151 . Treatment was also associated with improvement in histomorphometric features of mineralization defects 150 .

Adverse effects of burosumab treatment.
Burosumab treatment is well tolerated, with minor injectionsite reactions, pain in the extremities, fever, rash, myalgia and headaches reported 144 . In adults, restless legs syn drome (11.8%) was more frequently observed in the treated group than in the placebo group (7.6%) 149 .

Burosumab treatment in adults: recommendations.
• Burosumab could be suggested as a secondline ther apy in adults with XLH with overt osteomalacia, with pseudofractures that are not responding to conven tional treatment or in patients intolerant to conventional treatment.

Follow-up of patients with XLH.
Followup of both treated and untreated patients with XLH is an important aspect of management. A multidisciplinary team should be involved in the followup, and the examination and evaluation of the patient should be done at regular inter vals (Boxes 4,5). In addition, clearly identified pathways should exist for healthcare access in case of urgent clinical queries from both the patient and the patient's local healthcare team. This access is best facilitated by a nominated clinician or a clinical specialist nurse. The recommended clinical followup in children is shown in Boxes 4 and 5. As bonespecific ALP repre sents 90% of total circulating ALP in children, total ALP is a suitable biochemical parameter for the evaluation of rickets activity. In addition, the circulating levels of 25OHD and PTH should be followed, as vitamin D deficiency is frequent in these patients. Together with phosphate supplementation, vitamin D deficiency can stimulate secondary hyperparathyroidism. Of note, the use of active vitamin D metabolites is contraindicated in patients on burosumab treatment. The use of active vitamin D metabolites as part of conventional therapy is associated with the risk of hypercalcaemia and hypercal ciuria; therefore, patients need to be monitored closely to identify these biochemical abnormalities.
Severity of rickets can be assessed with plain radiog raphy examination of the wrist and/or knees. Systematic plain radiography is not recommended, but it should be done in children who are not responding to therapy, such as those with worsening of bone deformities despite medical treatment. Use of lowdose radiography (such as the EOS imaging system used in a standing posi tion) might be an option to limit radiation exposure. Other recommendations for monitoring are listed in Boxes 4 and 5.
Multidisciplinary approach Genetic counselling. XLH is transmitted in an Xlinked dominant manner. With each pregnancy, an affected woman has a 50% chance of passing the pathogenic PHEX variant to her child. Mosaicism could affect the expected transmission of the gene and rare instances of mosaicism in XLH have altered the expected transmission pattern 152 . An affected man passes the pathogenic variant to all of his daughters and to none of his sons. Offspring who receive the pathogenic variant will be affected; however, the severity of the phenotype cannot be firmly predicted because of large intrafamilial variations 3 .

Box 4 | Follow-up of children with XLH
Children with XlH should be seen at regular intervals by a multidisciplinary team: at least every 3 months during the phases of rapid growth or after initiation of therapy, at least every 6 months in patients showing a positive response to treatment and/or stable condition. Recommendations for follow-up assessments (radiological, biochemical and clinical) during these regular visits, or less frequently (as indicated) are provided.
• Perform radiographs a of the left wrist and/or knees if patients: do not respond well to therapy; show a worsening in their bone deformity under medical treatment; require orthopaedic surgery; or have unexplained bone pain. • Perform radiographs a of the left wrist and/or knees in adolescents with persistent lower limb deformities when they are transitioning to adult care. • measure height, weight, head circumference (in those aged <5 years), intercondylar distance and intermalleolar distance, and blood pressure. • measure BmI and annual height velocity.
• Search for hearing loss.
• monitor spine deformity and scoliosis, manifestations related to craniosynostosis, Chiari type 1 malformation and/or cranial hypertension, and maxillary dysmorphosis. • Record head shape, history of headaches, presence of dental abscesses or maxillofacial cellulitis, bone pain, fatigue and physical function. Prenatal testing for a pregnancy at increased risk can be considered if the PHEX pathogenic variant has been detected in the family 153 . In that case, as discussed above, targeted genetic testing can be done easily and inex pensively when the pathogenic variant in the relative is already known. Molecular genetic testing might include a single gene, such as PHEX sequencing, or a panel of sev eral genes causing genetic forms of hypophosphataemia (TaBle 1). If a pathogenic variant is not detected, further assessment can include genetargeted deletion or duplica tion analysis. For XLH, genetic diagnosis is established or confirmed by demonstrating a hemizygous PHEX patho genic variant in an individual with XY chromosomes and a heterozygous PHEX pathogenic variant in an individual with XX chromosomes.

Genetic counselling: recommendations.
• Genetic counselling is recommended for patients who have been diagnosed with XLH, to understand the risk of transmission. Genetic testing during pregnancy can be performed if the patient so wishes.
• Testing for XLH in newborn babies of families affected by XLH should also be done to prop erly diagnose the condition, as early as possible. Delayed diagnosis or misdiagnosis can result in delayed or no treatment and consequently in poor patient outcome.
Oral heath. Oral health is altered in patients with XLH. The disease impairs mineralization of the dentin and cementum 154 and also of the alveolar bone 155 . The most frequently reported complications are 'sponta neous' dental necrosis with severe abscesses that occur in deciduous or permanent teeth, with no history of trauma or decay. These episodes can evolve to maxillo facial cellulitis. The risk of periodontitis is also increased in adults with XLH, even in young adults, due to alter ations of the periodontal tissues 155 , which favours early tooth loss 137 .
Regarding dental features, enamel looks normal but is slightly thinner in patients with XLH and wears out more rapidly than sound enamel in healthy indi viduals, and displays microscopic cracks. The most affected tissue in XLH is the dentin. Radiographic den tal images from patients with XLH show low mineral density and enlarged pulp chambers. A characteristic sign is prominent pulp horns that extend to the den tal enamel junction 117,156 . Microscopically the dentin shows large unmineralized spaces with unmerged mineralization foci 157 . In these unmineralized spaces, peptides derived from small integrinbinding ligand Nlinked glycoproteins (known as SIBLINGs) accu mulate, such as Cterminal acidic serinerich and aspartaterich motif (ASARM) peptides derived from matrix extracellular phosphoglycoprotein (MEPE) and osteopontin abnormal cleavage, which are strong inhibitors of biomineralization 156,[158][159][160][161] . Taken together, these dental features explain the increased suscepti bility of patients with XLH to spontaneous necrosis and abscesses, whose origin is difficult to diagnose by medical practitioners and dentists not familiar with this disorder.
As stressed before, the earlier that conventional treatment is started in individuals with XLH during the growth period and in adulthood, the lower the incidence of dental abscesses 117 and periodontitis 137 . This effect occurs through an improvement in dentin and cementum mineralization as shown in observa tional studies 117,137 . The effects of burosumab on dental abnormalities are rather disappointing, with a phase III comparative study in children with XLH showing more events such as spontaneous dental necrosis in the burosumab arm than with conventional treatment 145 . A longer period of followup than carried out in this study might be required to observe a positive outcome on dentin and cementum mineralization. Overall, the quality of life of patients with XLH is strongly affected by dental events 162,163 .

Oral health: recommendations.
• Patients with XLH require specific and regular den tal examination (at least yearly) and appropriate care to prevent infections and early tooth loss, as well as

Box 5 | Follow-up of all patients with XLH
Patients with XlH should be seen at regular intervals by a multidisciplinary team: at least every 3 months during the phases of rapid growth or after initiation of therapy, at least every 6 months in patients showing positive response to treatment and/or stable condition. Recommendations for follow-up assessments (radiological, biochemical and clinical) for patients of any age with XlH during these regular visits, or less frequently (as indicated) are provided.
• In blood samples, monitor concentrations of AlP (total serum concentration of AlP in children and BAP in adults), calcium, phosphate, creatinine, PTH and 25oHD. • In urine, calculate the ratio of urinary calcium to creatinine in patients receiving conventional or burosumab treatment a . • In patients receiving burosumab treatment: -monitor fasting serum levels of phosphate together with the TmPi/GFR, every 2 weeks during the first month after treatment initiation, every 4 weeks for the following 2 months (and thereafter as appropriate). -measure fasting serum levels of phosphate 4 weeks after any dose adjustment.
-measure serum levels of 1,25(oH) 2 D every 6 months, analysed together with the urinary calcium excretion b as safety parameters. • Skeletal assessment -Perform cranial mRI in case of a skull morphology in favour of craniosynostosis or clinical signs of intracranial hypertension. In patients with persistent severe headache or other central nervous system symptoms, the mRI should also include the spinal column to identify potential syrinx. -Routine dual X-ray absorptiometry or peripheral quantitative CT are not recommended for assessment of bone health. • In treated patients: kidney ultrasonography should be performed at least every 2 years in patients without nephrocalcinosis, and at yearly intervals in patients with nephrocalcinosis and/or persistent hypercalciuria.
• Functional assessment: 6-min walk test and quality of life evaluation in patients aged >5 years (annual or 2-yearly intervals). • Provide the contact details of patient association groups to patients, to inform patients of scientific discoveries, including new therapies, to support school and professional input and to provide social support. aesthetic and functional damage, by a dental team with expertise in XLH 3 .
Orthopaedic intervention. Regular paediatric ortho paedic assessment during the growth period is recom mended in patients with XLH 3 . If surgery is needed, the orthopaedic surgeon can define the surgical plan and technique through a careful clinical examination, analy sis of the deformities with fulllength anteroposterior and lateral radiographs (hip to ankle) of both lower limbs in the standing position (with a calibration ball) and MRI. The type of orthopaedic management depends on the age of the patient and the type of deformity. Braces for deformity prevention with guidance of growth are no longer used in XLH because convincing evidence of efficacy is lacking 164 . The surgical options in XLH include guided growth, osteotomies, complex deformity corrections, internal fixation and stabiliza tion of pseudofractures, as well as joint replacement. Guided growth or temporary hemiepiphysiodesis are used to correct coronal deformity (valgus or varus). A small plate is fixed on the medial or lateral distal femur or proximal tibia that blocks the open growth plate. After successful correction, the plate is removed. This proce dure is effective in children and adolescents, minimally invasive and has a low rate of complications 165 . The pro cedure has been tested in patients with XLH 164,166-168 with success and could decrease the need of osteotomies. A limitation of this technique is that it needs growth potential. Furthermore, this technique corrects only the frontal deformity and cannot correct rotation or sagittal and diaphyseal bending of bone. A risk of recurrence is also present 169 .
Osteotomies are another option enabling 3D correc tion of complex deformities. Subsequent stabilization can be performed both using internal devices as well as external fixators. Osteotomies are required when epi physes are closed and guided surgery is no longer pos sible or in patients with complex deformities. Finally, arthroplasties of the hip and knee joints are possible in patients with XLH; however, these procedures require at times the simultaneous use of corrective osteotomies and special implants in patients with severe deformities 170,171 .
Diseasespecific gait deviations have been analysed in children and adults with XLH 111,172,173 ; however, they require further evaluation, as many patients with XLH report abnormal gait 84 . Of note, any orthopaedic surgery should be considered only in patients with XLH who are undergoing medical treatment that corrects the underly ing metabolic abnormalities, otherwise there is a notable risk of recurrence or failure of surgery. Patients who are considered for orthopaedic surgery should be referred to counselling services to prepare for and develop coping strategies for undertaking major surgery.
Symptomatic spinal cord compression due to spinal stenosis can be severe in patients with XLH and can occur at multiple levels. This complication might require neurosurgical posterior decompression and longterm followup 98 . Chiari malformations in children with XLH can progress in adulthood and lead to severe occipito cervical headache and a variety of respiratory symptoms, and are related to sudden unexpected death.

Patient organizations and research
Patients with XLH should be informed about the poten tial help and additional information that can be provided by patient organizations, and should be asked to contact them if needed. This information is particularly impor tant for the patient at the time the diagnosis is received. These organizations and patient representatives can share practical information about living with the con dition, and the usefulness and adverse effects of medi cations, and suggest support strategies for special needs. Sharing of information and educational materials, and provision of counselling or psychosocial support, are also critical for the parents of children with XLH or the partners of affected adult patients. For parents of a child with XLH, caring for the affected child can be extremely daunting and isolating, given the rarity of the disease and the lack of support networks and information available. For spouses or partners, the disease raises fundamental questions, including uncertainties about pregnancy and the risk and impact to both the mother and the child. Establishing patient networks and ensuring access to services including genetic counselling, psychologists and counsellors, are critical in the interdisciplinary approach.
In certain parts of the world, centres of expertise can have connections with patient representatives and patient organizations. These representatives and organ izations contribute to the planning, functioning and evaluation of these centres 174 . However, such centres can be absent in other parts of the world where mis diagnoses are still common, access to treatment is not readily available and support networks are scarce, if not nonexistent.
National guidelines issued from XLH centres of expertise should integrate and reflect patient prefer ences. In most clinical studies, treatment efficacy is evaluated through measurement of surrogate outcomes, such as serum levels of phosphate. However, how these surrogate outcomes relate to clinical benefits is unclear. Direct measures of patients' perceptions and feelings should be complementary to the evaluation of treatment effectiveness. Although diseasespecific measures of patientrelated outcome (PRO) are not available in XLH, conceptspecific instruments measuring pain, fatigue and physical function, for example, can be used -for example, the PatientReported Outcomes Measurement Information System measures 175 . Patient representatives and patient organizations are crucial in developing and establishing such measures. Such an instrument was used in a phase III clinical study of children with XLH and showed that burosumab improved PRO measures as compared with conventional treatment 175 . Finally, given the rarity of XLH, patients should be offered information about local, regional, national and international studies they might be eligible for.

Family members
As mentioned above, parents, legal guardians and/or family members have a critical role in supporting patients with XLH, even in those affected with only a mild form of the disease. It is paramount that they are also supported when caring for patients with XLH and have adequate access to information about the disease. This access is especially important given the rarity of this disease. For parents, especially those with XLH themselves, the burden starts even before the child is born. Having children can raise fundamental questions about the rate or risk of transmission, testing during pregnancy and treatment once the child is born. It also poses questions for the parents themselves; for example, to know if there are any known risks in pregnancy for women with XLH (beyond the 'usual' risks associated with pregnancy). Parents should be made aware of the physical, psychological, social and emotional effects of the disease, to support their child and to be able to cope themselves. The same goes for spouses, partners and other family members.

Conclusions
Given the diversity of symptoms and complications in XLH, an interdisciplinary approach is of paramount importance, with special mention paid to dental, orthopaedic, and psychological and emotional care. Multidisciplinary followup of patients with XLH is mandatory and should be coordinated by a metabolic bone disease specialist. Paediatric and adult patients should be evaluated twiceyearly by a dentist, and paedi atric patients should be followed up yearly by a paediatric orthopaedic surgeon specialized in XLH. Followup can involve dieticians, physiotherapists, occupational thera pists, social workers and psychologists. Physiotherapy and occupational therapy can be helpful after surgery or to treat musculoskeletal symptoms such as stiffness, muscular weakness and disability. A dietician can help in the prevention and treatment of obesity, which is highly prevalent in patients with XLH 102,110 . Patients should be referred to XLH patient organizations and patient repre sentatives for information and genetic counselling. The information they provide is particularly important when patients receive the diagnosis and at critical moments later in life (for example, when considering major life choices such as pregnancy). Interaction between patients, who can share their experiences, is important and could ensure optimal adherence to followup and therapy and thereby a successful outcome. Some impor tant unanswered questions remain to be explored in the area of the understanding of the pathogenesis of some complications of XLH or the effects of treatment (Box 6).

Box 6 | Remaining questions and research agenda
• To better understand the pathophysiology of enthesopathy and the putative impact of burosumab on this manifestation with earlier and/or longer duration of use in the life-course than in current trials. • To evaluate the mechanism of obesity and hypertension in children and adults with XlH and their effect on mortality. • To further assess and document the risks and effects of XlH during pregnancy, for both the pregnant individual and the child. • To assess the long-term effects of burosumab treatment, as well as the effects of starting the treatment before 1 year of age and its use during adolescence, on: lower-limb deformities and the need for surgical treatment; adult height; dental complications and abscess incidence; sensorineural hearing loss; pseudofracture prevention; craniosynostosis; and muscle function. • To develop a specific and adequate physiotherapy programme for patients with XlH, aimed at reducing disabilities and disease burden. • To develop guidelines on measures to improve motor function, to meet the needs of patients. • To develop cohort studies to evaluate the natural history and the effect of burosumab on rare complications. • To define the optimal serum concentration of phosphate to reduce disease burden.