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Wien Med Wochenschr (2020) 170:116–123https://doi.org/10.1007/s10354-019-00732-2

Multidisciplinary patient care in X-linked hypophosphatemicrickets: one challenge, many perspectives

Adalbert Raimann · Gabriel T. Mindler · Roland Kocijan · Katrin Bekes · Jochen Zwerina · Gabriele Haeusler ·Rudolf Ganger

Received: 24 September 2019 / Accepted: 17 December 2019 / Published online: 28 January 2020© The Author(s) 2020

Summary X-linked hypophosphatemic rickets (XLH,OMIM #307800) is a rare genetic metabolic disordercaused by dysregulation of fibroblast-like growth fac-tor 23 (FGF23) leading to profound reduction in re-nal phosphate reabsorption. Impaired growth, se-vere rickets and complex skeletal deformities are di-rect consequences of hypophosphatemia represent-ing major symptoms of XLH during childhood. Inadults, secondary complications including early de-velopment of osteoarthritis substantially impair qual-ity of life and cause significant clinical burden. Withthe global approval of the monoclonal FGF23 anti-body burosumab, a targeted treatment with promis-ing results in phase III studies is available for childrenwith XLH. Nevertheless, complete phenotypic rescueis rarely achieved and remaining multisystemic symp-toms demand multidisciplinary specialist care. Co-ordination of patient management within the major

A. Raimann (�) · G. HaeuslerComprehensive Center for Pediatrics, Department ofPediatrics and Adolescent Medicine, Division of PediatricPulmonology, Allergology and Endocrinology, MedicalUniversity of Vienna, Vienna, Austriaadalbert.raimann@meduniwien.ac.at

G. T. Mindler · R. GangerDepartment of Pediatric Orthopaedics, OrthopaedicHospital Speising, Vienna, Austria

R. Kocijan · J. ZwerinaHanusch Hospital of the WGKK and AUVA Trauma Center,1st Medical Department at Hanusch Hospital, LudwigBoltzmann Institute of Osteology, Vienna, Austria

K. BekesDepartment of Pediatric Dentistry, School of Dentistry,Medical University of Vienna, Vienna, Austria

A. Raimann · G. T. Mindler · R. Kocijan · J. Zwerina ·G. Haeusler · R. GangerVienna Bone and Growth Centre, Vienna, Austria

medical disciplines is a mainstay to optimize treat-ment and reduce disease burden. This review aimsto depict different perspectives in XLH patient care inthe setting of a multidisciplinary centre of expertisefor rare bone diseases.

Keywords XLH · Burosumab · Rare disease ·Phosphate · FGF23

Multidisziplinäre Patientenversorgung bei X-chromosomaler hypophosphatämischerRachitis: Perspektiven einer klinischenHerausforderung

Zusammenfassung Die X-chromosomale hypophos-phatämische Rachitis („X-linked hypophosphatemicrickets“, XLH: OMIM #307800) ist eine seltene gene-tische Erkrankung des Knochenstoffwechsels. Durcheine Dysregulation von „fibroblast-like-growth fac-tor 23“ (FGF23) kommt es zu einem ausgeprägtenrenalen Phosphatverlust, der sich im Kindesalter mitreduziertem Längenwachstum, schwerer Rachitis undDeformitäten der Extremitäten manifestiert. Im Er-wachsenenalter tragen das frühe Auftreten von Ar-throse sowie chronische skeletale Schmerzen zurhohen Morbidität der Patienten bei. Seit der weltwei-ten Zulassung eines monoklonalen Antikörpers gegenFGF23, Burosumab, mit vielversprechenden Ergebnis-sen in Phase-III-Studien steht erstmals eine kausaleTherapieoption für pädiatrische Patienten mit XLHzur Verfügung. Aufgrund der meist bestehenden Rest-symptomatik ist die spezialisierte multidisziplinäreVersorgung der Patienten trotz Fortschritten in derBehandlung die essenzielle Grundlage in der langfris-tigen Betreuung der Patienten. Dabei spielt die Koor-dination der Behandlung innerhalb der wesentlichenmedizinischen Fachgebiete eine wichtige Rolle für dieoptimale Therapie und Senkung der Krankheitslast.

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Diese Übersichtsarbeit gibt die verschiedenen Per-spektiven der Versorgung von Patienten mit XLH ausSicht von Mitgliedern eines nationalen Expertisezen-trums für seltene Knochenerkrankungen wieder.

Schlüsselwörter Phosphatdiabetes · Burosumab ·Seltene Erkrankung · Phosphat · FGF23

Background

Pathophysiology

X-linked hypophosphatemic rickets (XLH) is causedby loss-of-function of PHEX (phosphate-regulatinggene with homology to endopeptidases on the X chro-mosome) and represents the most common form ofhereditary hypophosphatemic rickets with a preva-lence of 1/20000 newborns [1]. XLH is characterizedby profound hypophosphatemia due to increasedlevels of a key a regulator of phosphate handling,fibroblast-like growth factor 23 (FGF23).

On a cellular level, FGF23 and its coactivator alpha-Klotho bind to fibroblast-like growth factor receptors(FGFRs) such as FGFR1 and regulate phosphate han-dling by two independent mechanisms [2]. In theproximal renal tubule, FGF23 inhibits phosphate re-absorption by downregulation of type II sodium/phosphate cotransporters (NaPi2a and NaPi2c)[3].Further, an indirect reduction of intestinal resorp-tion is exerted by downregulating 25-hydroxyvitaminD-1α-hydroxylase activity and suppression of 1,25 di-hydroxy-vitamin D (1,25OHD) levels [4]. Thus, en-docrine FGF23 represents the major link betweenphosphate storage in calcified tissues and nutritionalphosphate handling and allows the body to react tohigh phosphate intake as well as to higher phosphateneeds during growth periods. While bone representsthe main source of endocrine FGF23, expression canbe detected in multiple tissues with a so far mostlyunclear role in health and disease [5, 6].

Clinical manifestation

In XLH, loss-of-function of the PHEX endopeptidaseleads to an overexpression of FGF23 by unknownmechanisms. Major symptoms of XLH reflect thechronic hypophosphatemia. The development ofa varus deformity of the lower limbs (bow legs) atthe onset of gait is a common initial symptom ofXLH. However, in toddlers it has to be distinguishedfrom physiological bow legs, which can delay thediagnosis. Skeletal hypomineralization and rachiticgrowth plates typically lead to progressive varus orvalgus deformities of the lower extremities. Torsionaldeformities, especially increased internal tibial tor-sion, lead to intoeing gait and impaired gait patterns.Despite optimal treatment, patients with XLH of-ten exhibit significantly impaired longitudinal growthdue to pathologic changes of the growth plates. Body

height is additionally impacted by deformities of thelower limb, resulting in short stature in adulthoodin a substantial number of patients with XLH. Dueto relatively normal growth of the spine, dispropor-tion is a common feature. Musculoskeletal pain andmuscular weakness further impact motional functionand often lead to hypomobility with an associatedincrease in body weight. Although less common,increased intracranial pressure and craniosynostosisbecause of dysregulated ossification are importantsymptoms and need neurological and neurosurgicalcare.

Dentin hypomineralization causes a high rate ofendodontic infections, which can occur already inearly childhood despite optimal dental care [7]. Othersymptoms of the musculoskeletal apparatus suchas enthesopathies, early onset of osteoarthritis andspinal deformities mainly develop in adulthood andcontribute to a significant impact on quality of life andsocial participation. As the pathomechanism of someof these symptoms cannot be entirely explained byhypophosphatemia, treatment options often remainsymptomatic.

Patient management

The variety of symptoms in patients with XLH ne-cessitates tight coordination of multidisciplinary pa-tient care to optimize quality of life and reduce dis-ease burden. This review aims to depict the currentstate of patient management from the perspectives ofthree central disciplines involved in XLH patient care,necessitating an age-related and individual treatmentapproach (Fig. 1).

XLH—a paediatric perspective

Based on the recent publication of systematicallydeveloped recommendations on diagnosis and treat-ment of XLH, standardized management by multi-disciplinary teams organized by a metabolic bonedisease expert represents the mainstay of XLH patientcare [8]. Due to its manifestation and onset of mainsymptoms during early childhood, paediatricians andpaediatric orthopaedic surgeons play a special rolein guiding patients and coordinating expert teamsthroughout the critical phase of linear growth.

Diagnosis of XLH in children

XLH is diagnosed by clinical, radiologic and biochem-ical symptoms. As 20% of cases are non-familialdue to de novo mutations, early diagnosis is a keychallenge in paediatric patients [9]. Imaging revealsrachitic lesions with typical fraying and cupping ofthe growth plates. Biochemical characteristics in pa-tients with XLH include decreased serum phosphate,increased ALP levels and elevated or inappropriatelynormal FGF23. The rachitic phenotype of XLH is fre-

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Fig. 1 Schematic overviewof treatment goals andmodalities in paediatric andadult patients with X-linkedhypophosphatemic rickets(XLH)

quently misdiagnosed as nutritional rickets, skeletaldysplasia or Blount’s disease. While subtle differencesin X-rays exist, such as lack of bone translucencywith a prominent cortical compartment, XLH andnutritional rickets are often difficult to differentiateon X-rays.

Biochemical investigations easily discriminate XLHfrom other diagnoses: serum phosphate levels areusually below the normal, though age-specific nor-mal ranges have to be considered. In contrast tothe most common misdiagnosis, nutritional rickets,ALP levels in XLH are lower than to be expected insevere vitamin D deficiency with severe deformities.Further, PTH levels are commonly about the uppernormal range at diagnosis of XLH while being typi-cally elevated in nutritional rickets. Inappropriatelyhigh FGF23 levels might further contribute to diag-nostics but are costly and often not readily available.Regarding urine analysis, renal phosphate wasting canbe confirmed by calculation of the tubular maximumreabsorption of phosphate per glomerular filtrationrate (TmP/GFR) and represents a powerful and eco-nomic diagnostic measure [10]. Finally, detection ofpathogenic PHEXmutations confirms the diagnosis ofXLH, although mosaicism and intronic mutations canlead to negative results. Phenotype–genotype relationis weak, raising the importance of evaluation of familymembers for symptoms.

Although the onset of symptoms commonly occursduring early childhood, patients might be referred pri-marily to orthopaedic evaluation because of extremitydeformities despite lack of nutritional rickets. Other

specific symptoms such as endodental abscesses inearly childhood are characteristic for XLH and shouldalways warrant further evaluations. Thus, tight co-operation with paediatric orthopaedics, dentists andother involved disciplines are essential to minimizediagnostic delays and initiate treatment as early aspossible.

Medical treatment

Treatment should be established at best at early in-fancy, since early treatment is associated with betteroutcome [11]. Two different types of therapy exist.Conventional treatment consists of frequent dosagesof oral phosphate salts combined with active vita-min D derivates such as calcitriol or alfacalcidol.Increased availability of phosphate improves bonemineralization and ameliorates skeletal symptoms[5]. The short biologic half-life of oral phosphatenecessitates frequent dosages up to six times/day.Thus, compliance to treatment represents a majorissue. While phosphate availability increases, FGF23levels are further increased by treatment and seriousside effects such as hyperparathyroidism and nephro-calcinosis occur frequently. The balance betweenoptimization of skeletal symptoms and minimizationside effects is challenging and requires frequent visits.

Since its registration by EMA and FDA, the mono-clonal antibody burosumab has represented a noveltherapeutic option. Burosumab directly binds FGF23and directly targets the main pathomechanism ofXLH and can normalize phosphate excretion. A re-

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cent phase III study could prove superiority of an-tibody treatment to conventional therapy regardingradiological improvement as the main study end-point [12]. Although the patient inclusion criteria ofthis study limit conclusions on superiority in mildly/moderately affected individuals, burosumab broad-ens the therapeutic horizon especially for severelyaffected children and patients with insufficient re-sponse to conventional treatment. Long-term studieswill be needed to judge the impact of this new ther-apy on major clinical burdens such as deformitiesand numbers of surgeries needed.

While current treatment studies focus on improve-ment of rachitic changes in order to prevent progres-sion of deformities and optimize growth, a multitudeof symptoms with less-defined metrics impair qualityof life of patients.

Dental-related patient findings in patients withXLH are recurrent abscesses or sinus tracts associatedwith carious free teeth of primary and permanentdentition. Additionally, delayed tooth eruption occursboth in the primary and in the permanent dentition.Radiographically, very large pulp chambers, suggest-ing taurodontism, are often evident. Affected teethshow a thin enamel layer and dentinal defects as wellas short roots and root resorptions in the primarydentition [13]. In contrast to systemic effects, dentalsymptoms appear not to be FGF23 driven but directlycaused by local effects of extracellular matrix compo-nents due to impaired PHEX function [14]. Althoughimprovement of dental abscesses has been reportedunder conventional therapy at least in adults [15],FGF23-blocking antibody treatment studies did notinvestigate dental symptoms in detail and did notreveal a reduction in dental symptoms in adverseevents. The main primary treatment options in thesepatients are frequent dental controls and professionaldental care, especially focusing on the prevention ofattrition due to the fact that the structure of dentalhard tissues is severely altered [13].

Bone pain is another common and challengingsymptom in patients with XLH. Recent studies showprevalence of quality of life-impairing pain in 65–80%of all paediatric patients with XLH [16, 17]. Althoughimprovement of rachitic changes by medical treat-ment is associated with amelioration of pain [8], fur-ther pain-relieving measures might be necessary toallow social participation and facilitate regular motordevelopment. Involvement of specialized functionaltherapists may reduce symptoms and mobility im-pairment. In the context of overweight and obesityaffecting 1/3 of children with XLH [18], any poten-tially achievable increase in physical activity levelsis of great value in this patient group. Similar toother conditions associated with chronic pain, psy-chological support should be offered. Socioeconomicburdens additional to physical symptoms of the dis-ease might hamper integration in regular schools

and working life, thus social work is needed to assistpatients and caretakers.

Follow-up

Follow-up of children and adolescents with XLH in-cludes clinical, biochemical and radiologic assess-ments to adjust conventional treatment and balanceskeletal healing with complications such as hyper-parathyroidism and nephrocalcinosis. In contrastto conventional therapy, burosumab-treated patientsare targeted to reach serum phosphate values in thenormal range and have to be dose-adjusted accord-ingly. While the reliability of the Rickets Severity Score(RSS) has recently been proven in patients with XLH[19], imaging of rachitic signs is often performed atsingle skeletal sites only to reduce radiation exposure.Quality of life should be assessed regularly to deter-mine impact on everyday life and identify individualclinical burdens. Detailed recommendations on fol-low-up investigations are available in evidence-basedconsensus guidelines, ameliorating standardization ofcare and adaption of local follow-up protocols to thecurrent state of clinical science [8] (follow-up scheme:Table 1).

XLH—an adult osteological perspective

XLH in adults is associated with several musculoskele-tal symptoms including osteomalacia, enthesopathyandmuscle weakness. Almost all adults report bone orjoint pain, and nearly every second adult XLH patienthas already sustained a fracture [17]. Extra-skeletalmanifestations include dental complications (e.g. pe-riodontitis) and hearing loss. Consequently, quality oflife in XLH patients is often severely impaired. Typicalradiographic features in adult patients with XLH arepseudofractures and osteoarthritis of the spine andjoints. Calcifications of ligaments and enthesopathiescan also be detected by X-ray examinations.

Diagnosis of XLH in adults

Based on recent recommendations for the manage-ment of X-linked hypophosphatemia, the diagnosis ofXLH in adults should be considered in case of typicalclinical or radiological signs and low levels of serumphosphate as well as renal phosphate wasting [8].A positive family history for XLH is indicative. Theclinical diagnosis can be confirmed by genetic testing.Usually alkaline phosphatase (ALP) and intact FGF23levels are increased. However, FGF23 levels can benormal in XLH, and high FGF23 levels can also befound in other diseases [8]. Differential diagnosis ofhigh serum FGF23 levels include fibrous dysplasia,autosomal dominant or recessive hypophosphatemicrickets and Raine syndrome [20].

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Table 1 XLH follow-upplan for paediatric patients ViennaBone and Growth Centre. (Based on [1, 7, 8])

XLH patient management plan Vienna Bone andGrowth Centre

Interval

Clinical monitoring

Including height, BMI, BP, head circumference, deformity monitoring,neurological examination

Rapid growth phases 3-monthly

Significant treatment changes 3-monthly

Stable phase 6-monthly

Quality of life monitoring

PedsQL 3–6-monthly

VAS 3-monthly

Functional monitoring

6MWT 12-monthly

PEDI-D 24-monthly

Lab monitoring

Conventional treatment

Ca, P, Ca/Crea ratio, ALP 3-monthly

PTH, 25(OH)D 6-monthly

Burosumab

Initial phase: P, Ca, TmP/GFR Week 2, 4, 8, 12

Stable phase: P, Ca, TmP/GFR 3-monthly

PTH, 25(OH)D, 1,25(OHD), UCa/Crea 6-monthly

Bone imaging 12–24-monthly

Kidney ultrasound

Regular findings 24-monthly

Hypercalciuria/nephrocalcinosis 12-monthly

Orthopaedic monitoring 6–12 monthly

Dental monitoring 6-monthly

Cranial MRI If indicated

Cardiac ultrasound If hypertensive

XLH X-linked hypophosphatemic rickets, BMI body mass index, BP bloodpressure, PedsQL pediatric quality of life inventory, VAS visual analoguescale, MWT 6 minute walking test, PEDI-D pediatric evaluation of dis-ability inventory, Ca calcium, P phosphate, Crea creatinine, ALP alkalinephosphatase, PTH parathyroid hormone, TmP/GFR ratio of the maxi-mum rate of tubular phosphate reabsorption to glomerular filtration rate,25(OH)D 25-hydroxycholecalciferol, 1,25(OHD) 1,25-dihydroxycholecalcif-erol, UCa/Crea urinary calcium to creatinine ratio

Management of adult XLH patients

Management of adult XLH patients includes regularlaboratory and radiological examinations as well as as-sessment of pain, muscle strength, mobility and treat-ment response. An important part of adult XLH careis the transition from the paediatric clinic to the de-partment of internal medicine. Specific requirementsand individual needs of adult XLH patients must beobserved. Specialists for internal medicine, rehabil-itation medicine, dentistry and orthopaedic surgeryare therefore involved in the management of adultXLH patients. An XLH support group was recentlyfounded in Austria to give patients the opportunity toexchange their experiences and to facilitate their lives(www.phosphatdiabetes.at).

Medical treatmentMedical treatment in adult XLH patients is quite sim-ilar to that in children with XLH, including phosphateand active vitamin D substitution. Conventional treat-ment in adults is only recommended in symptomaticpatients [1]. In asymptomatic adult XLH patients,treatment does not seem to be beneficial. However,based on recent recommendations, treatment shouldalso be considered in case of planned orthopaedic ordental surgery or evidence of osteomalacia [8].

Although a positive effect of conventional therapyon pain, osteomalacia and oral health has been sug-gested, phosphate and active vitamin D substitutiondo not prevent the occurrence of enthesopathies [21].Anti-resorptive drugs including bisphosphonates anddenosumab must be avoided. For teriparatide, an os-teoanabolic agent, there are no data available in XLH.Calcium supplementation is not recommended.

In Europe, burosumab—a anti FGF23 antibody—iscurrently approved for treatment of children withXLH. However, promising data have already been pub-lished for adults. A normalization of phosphate levelsand an improvement in fracture healing was shownunder anti-FGF23 antibody therapy [22]. Treatmentcontinuation of burosumab improved pain, stiffnessand physical function in adult patients with XLH [23].

The effect of burosumab on osteomalacia waspublished recently. In this paired bone biopsy study,48 weeks of burosumab treatment resulted in animprovement of osteomalacia-related histomorpho-metric parameters [24].

Follow-up of adult XLH patientsFollow-up examinations should include ALP, calcium,phosphate, creatinine, parathyroid hormone (PTH)and 25(OH) vitamin D. Moreover, screening for skele-tal manifestations as well as blood pressure, dentaldisease, pain, fatigue and muscular strength are rec-ommended [8]. In patients receiving therapy, a renalultrasound should be performed in order to excludekidney stone disease [1]. Dental-related symptoms,as mentioned in the paediatric perspective, urge forfrequent checks at specialized centres to minimizetooth loss and dental abscesses. In contrast to otherbone diseases, bone mineral density (BMD) measure-ments by DXA scanning do not play a major rolein the diagnosis or follow-up of adult XLH patients.A high trabecular BMD can be observed in most XLHpatients. In contrast, cortical BMD is usually low [25].Serum FGF23 levels are useful in untreated individu-als but cannot guide treatment decisions in patientsreceiving adequate therapy.

Differential diagnosis of low phosphate levels inadults

It must be considered that low phosphate levelsand skeletal symptoms in adults might have sev-eral reasons. Tumour-induced osteomalacia (TIO)

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Fig. 2 Accurate preoperative deformity analysis allowsan optimizes surgical treatment approach in patients withX-linked hypophosphatemic rickets

is caused mainly by mesenchymal tumours and isassociated with low phosphate levels due to paraneo-plastic FGF23 overproduction [26]. In general, TIO iscurable if the tumour can be removed [27]. In case ofunresectable or unidentifiable tumour, a conservativetreatment should be initiated. A case of TIO due tomeningioma and effective burosumab treatment waspublished recently [28]. Moreover, several drugs suchas adefovir or intravenous iron therapy can lead tohypophosphatemia and similar symptoms to XLH [29,30]. Therefore, TIO, drug-induced hypophosphatemiaand other forms of osteomalacia and renal tubularphosphate wasting must also be considered in adultpatients with low phosphate levels.

XLH—a paediatric orthopaedic perspective

The paediatric orthopaedic treatment of patients withXLH can be a challenging task with the goal of pre-vention and treatment of deformity. Decision-makingfor the right surgical treatment and its optimal timingis more complex in patients with XLH than in otherpaediatric orthopaedic aetiologies.

Diagnostics

An accurate physical examination with focus on gait,rotational profile of the lower legs and range of motionof the joints is the cornerstone of further diagnostic

measures. Basic radiographic examination is obtainedwith a long-leg standing X-ray. This view enables usto detect joint abnormalities, leg length discrepancies,multiapical bone deformities and deviation of the axis(varus or valgus). Furthermore, the lateral view of thelower leg is important to detect eventual masked de-formities. As torsional deformities of bones are quitecommon in patients with XLH torsion, MRI (preferredmethod) or CT can be helpful for preoperative plan-ning. Additional information on compensation mech-anisms can be gained using 3D gait analysis.

Surgical treatment plans need individual, carefuland comprehensive preoperative deformity analysis.Multiple angles on standing X-rays have to be mea-sured to choose the right surgical technique and theaccurate amount of correction (Fig. 2; [31, 32]). Differ-ent software programs such as Trauma CAD software(Voyant Healt, Petach-Tikva, Israel) or the Bone Ninja(Rubin Institute for Advanced Orthopedics, Sinai Hos-pital of Baltimore; Baltimore, MD, USA) app can helpto analyse the deformity and make our treatmentplans more understandable for our patients.

Orthopaedic management

Adequate basic medical treatment and physiotherapyare the best conservative treatment options. Pain canbe a sign for inadequate medication and does notnecessarily correlate with bony deformity, especiallyin younger children. Critical observation with regularclinical and radiographic follow-up in cases of bor-derline deformity are the main paediatric orthopaedicactivities during growth.

Historically, long leg braces were thought to pre-vent deformity in children with XLH. However, thereis no scientific evidence to support the use of bracesto guide growth in children with XLH [33]. The pae-diatric orthopaedic surgeon needs a comprehensiveknowledge of physiological and pathological growth,of deformity analysis and deformity correction, andneeds to be trained in the different surgical proce-dures. Various surgical procedures with differencesin the amount of achievable correction, complicationprofile and quality of life are used to treat lower limbdeformity in children with XLH.

Surgical treatment options

Guided growth with hemiepiphysiodesis is a mini-mally invasive treatment option for mild deformitiesof the lower limbs. Several studies showed favourableresults in children with healthy and pathological ph-ysis [34–36]. Depending on the deformity, the growthplate is temporarily blocked using a small plate withtwo screws on the medial or lateral distal femur orproximal tibia. However, torsional deformities can-not be treated with this method. Children with XLHhave to be younger for this technique, due to reducedgrowth velocity and therefore reduced correction po-

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tential. The procedure requires open growth platesand a second operation to remove the implant afterfull correction.

Promising postoperative results in children withXLH treated with hemiepiphysiodesis have beenreported [33, 37, 38] and combined with carefulmetabolic control, this method can prevent the needfor osteotomies [38]. However, a higher failure rate inchildren with XLH has been described [39]; neverthe-less, the method can be repeated safely.

A more invasive method to correct lower limb de-formities are osteotomies with different types of fix-ation. Deformities can be corrected acutely or grad-ually. In acute deformity correction the osteotomyhas to be stabilized using plates and screws or in-tramedullary nails. In younger children, wires in com-bination with a cast can be used. More complex defor-mities need to be corrected gradually. A unilateral orring fixator can be used for external fixation and grad-ual lengthening and/or axis correction. Even most se-vere deformities can be treated safely with an externalring fixator. It takes several months until the bone isperfectly healed and the frame is removed. A moreconvenient method uses intramedullary lengtheningnails which allow deformity correction and length-ening of bones. Technical limitations of these in-tramedullary implants are the severe bowing of thefemora and tibiae often seen in XLH patients.

Recurrence of deformity after surgery can occur ir-respective of the method used in children with XLH,and needs to be treated adequately. Rehabilitation af-ter surgery in patients with XLH is a multidisciplinaryeffort, especially when external fixators are used. Ad-equate metabolic control, appropriate pain manage-ment, devices for mobility and individual physiother-apy by specially trained physiotherapists are necessaryto achieve high patient satisfaction and best postoper-ative results. Psychologic counselling and the possibil-ity to attend school during the time of hospitalizationare extraordinarily important in a paediatric surgicaltreatment setting.

Conclusion

In amultisystemic disorder such as XLH,managementand integration of specialized subdisciplines is ofgreat importance to minimize long-term sequalae andoptimize quality of life. Recent advances in pharma-cologic therapy of XLH as well as refined orthopaedictechniques contribute to improve skeletal symptoms.Nevertheless, most patients remain symptomatic andmore specific treatment approaches, especially forlife-impairing symptoms such as bone pain, enthe-sopathies and dental problems, are needed. Theformation of multidisciplinary expert centres, as wellas the implementation of individualized patient careand transnational clinical studies will further help totarget remaining challenges in the management ofXLH.

Funding Openaccess fundingprovidedbyMedicalUniversityof Vienna.

Conflict of interest A. Raimann, G.T. Mindler, R. Kocijan,K. Bekes, J. Zwerina, G. Haeusler and R. Ganger declare thatthey have no competing interests.

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References

1. CarpenterTO,ImelEA,HolmIA,JandeBeurSM,InsognaKL.A clinician’s guide to X-linked hypophosphatemia. J BoneMinerRes. 2011;26(7):1381–8.

2. GattineniJ,TwombleyK,GoetzR,MohammadiM,BaumM.Regulationof serum1,25(OH)2VitaminD3 levelsbyfibrob-last growth factor 23 ismediated by FGF receptors 3 and 4.AmJPhysiol. 2011;301(2):F371–7.

3. Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M,KusanoK, etal. Effectofhydrolysis-resistantFGF23-R179Qon dietary phosphate regulation of the renal type-II Na/Pitransporter. PflugersArch. 2003;446(5):585–92.

4. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R,Takeuchi Y, et al. FGF-23 is a potent regulator of vitaminDmetabolismandphosphatehomeostasis. JBoneMinerRes.2004;19(3):429–35.

5. Raimann A, Ertl DA, Helmreich M, Sagmeister S,Egerbacher M, Haeusler G. Fibroblast growth factor 23andKlotho arepresent in the growthplate. Connect TissueRes. 2013;54(2):108–17.

6. FaulC.Fibroblastgrowth factor 23andtheheart. CurrOpinNephrolHypertens. 2012;21(4):369–75.

7. LinglartA,Biosse-DuplanM,BriotK,ChaussainC,EsterleL,Guillaume-Czitrom S, et al. Therapeutic managementof hypophosphatemic rickets from infancy to adulthood.EndocrConnect. 2014;3(1):R13–R30.

8. HaffnerD,EmmaF,EastwoodDM,DuplanMB,Bacchetta J,Schnabel D, et al. Clinical practice recommendationsfor the diagnosis andmanagement of X-linked hypophos-phataemia. Nat Rev Nephrol. 2019; https://doi.org/10.1038/s41581-019-0152-5.

9. WhyteMP, Schranck FW, Armamento-Villareal R. X-linkedhypophosphatemia: asearchforgender, race,anticipation,orparentoforigineffectsondiseaseexpression inchildren.JClinEndocrinolMetab. 1996;81(11):4075–80.

10. Brodehl J, Krause A, Hoyer PF. Assessment of maximaltubular phosphate reabsorption: comparison of directmeasurement with the nomogram of Bijvoet. PediatrNephrol. 1988;2(2):183–9.

11. Mäkitie O, Doria A, Kooh SW, Cole WG, Daneman A, So-chett E. Early treatment improves growth and biochemicaland radiographicoutcome inX-linkedhypophosphatemicrickets. JClinEndocrinolMetab. 2003;88(8):3591–7.

122 Multidisciplinary patient care in X-linked hypophosphatemic rickets: one challenge, many perspectives K

main topic

12. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM,NilssonO,etal. Burosumabversusconventional therapy inchildrenwithX-linkedhypophosphataemia: arandomised,active-controlled, open-label, phase 3 trial. Lancet.2019;393(10189):2416–27.

13. Sabandal MMI, Robotta P, Bürklein S, Schäfer E. Reviewof thedental implications of X-linkedhypophosphataemicrickets(XLHR).ClinOral Invest. 2015;19(4):759–68.

14. Coyac BR, Hoac B, Chafey P, Falgayrac G, Slimani L,Rowe PS, et al. Defective mineralization in X-linked hy-pophosphatemia dental pulp cell cultures. J Dent Res.2018;97(2):184–91.

15. Econs MJ. Conventional therapy in adults with XLH im-provesdental manifestations, but not enthesopathy. J ClinEndocrinolMetab. 2015;100(10):3622–4.

16. Emma F, Cappa M, Antoniazzi F, Bianchi ML, Chiodini I,Eller Vainicher C, et al. X-linked hypophosphatemic rick-ets: an Italian experts’ opinion survey. Ital J Pediatr.2019;45(1):67–31.

17. Skrinar A, Dvorak-Ewell M, Evins A, Macica C, Linglart A,Imel EA, et al. The lifelong impact of X-linked hypophos-phatemia: results fromaburdenofdiseasesurvey. JEndocrSoc. 2019;3(7):1321–34.

18. Zhukouskaya V, Lambert A-S, Rothenbuhler A, Colao A, DiSommaC,KamenickyP,etal. SAT-259naturalhistoryofan-thropometric parametres of obesity in children affected byX-linked hypophosphatemia: longitudinal obserbationalstudy. JEndocrSoc. 2019;3(Suppl1):SAT-259.

19. Thacher TD, Pettifor JM, Tebben PJ, Creo AL, Skrinar A,Mao M, et al. Rickets severity predicts clinical outcomesin childrenwith X-linkedhypophosphatemia: utility of theradiographicricketsseverityscore. Bone. 2019;122:76–81.

20. Huang X, Jiang Y, Xia W. FGF23 and phosphate wastingdisorders. BoneRes. 2013;1(2):120–32.

21. Connor J, Olear EA, Insogna KL, Katz L, Baker S, Kaur R, etal. Conventional therapyinadultswithX-linkedhypophos-phatemia: effects on enthesopathy and dental disease.JClinEndocrinolMetab. 2015;100(10):3625–32.

22. Insogna KL, Briot K, Imel EA, Kamenický P, Ruppe MD,Portale AA, et al. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of Buro-sumab, an anti-FGF23 antibody, in adults with X-linkedHypophosphatemia: week 24 primary analysis. J BoneMinerRes. 2018;33(8):1383–93.

23. Portale AA, Carpenter TO, Brandi ML, Briot K, Cheong HI,Cohen-Solal M, et al. Continued beneficial effects ofBurosumab in adults with X-linked hypophosphatemia:results froma24-week treatment continuationperiodaftera 24-week double-blind placebo-controlled period. CalcifTissueInt. 2019;105(3):271–84.

24. Insogna KL, Rauch F, Kamenický P, Ito N, Kubota T, Naka-mura A, et al. Burosumab improved histomorphomet-ric measures of osteomalacia in adults with X-linked hy-pophosphatemia: aphase3,single-arm, international trial.J Bone Miner Res. 2019; https://doi.org/10.1002/jbmr.3843.

25. CheungM, Roschger P, Klaushofer K, Veilleux L-N, Rough-leyP,GlorieuxFH,etal. Corticalandtrabecularbonedensityin X-linked hypophosphatemic rickets. J Clin EndocrinolMetab. 2013;98(5):E954–E61.

26. Yin Z, Du J, Yu F, Xia W. Tumor-induced osteomalacia.OsteoporosSarcopenia. 2018;4(4):119–27.

27. Mishra SK, Kuchay MS, Sen IB, Garg A, Baijal SS, Mithal A.Successful management of tumor-induced osteomalaciawith radiofrequency ablation: a case series. JBMR Plus.2019;https://doi.org/10.1002/jbm4.10178.

28. Day AL, Gutiérrez OM, Guthrie BL, Saag KG. Burosumabin tumor-induced osteomalacia: a case report. Joint BoneSpine. 2019;https://doi.org/10.1016/j.jbspin.2019.07.012.

29. Koda R, Tsuchida M, Iino N, Narita I. Hypophosphatemicosteomalacia associated with adefovir-induced Fanconisyndrome initially diagnosed as diabetic kidney diseaseandvitaminDdeficiency. InternMed. 2019;58(6):821–5.

30. Bartko J, Roschger P, Zandieh S, Brehm A, Zwerina J,Klaushofer K. Hypophosphatemia, severe bone pain, gaitdisturbance, and fatigue fractures after iron substitution ininflammatory bowel disease: a case report. J Bone MinerRes. 2018;33(3):534–9.

31. Paley D, Herzenberg JE, Tetsworth K, McKie J, Bhave A.Deformityplanning for frontalandsagittalplanecorrectiveosteotomies. OrthopClinNorthAm. 1994;25(3):425–65.

32. PaleyD,TetsworthK.Mechanicalaxisdeviationof thelowerlimbs. Preoperative planning of multiapical frontal planeangularandbowingdeformitiesof thefemurandtibia. ClinOrthopRelatRes. 1992;280:65–71.

33. Novais E, Stevens PM. Hypophosphatemic rickets:the role of hemiepiphysiodesis. J Pediatr Orthop.2006;26(2):238–44.

34. StevensPM,KlattJB.Guidedgrowthforpathologicalphyses:radiographic improvement during realignment. J PediatrOrthop. 2008;28(6):632–9.

35. Saran N, Rathjen KE. Guided growth for the correction ofpediatric lower limb angular deformity. J Am Acad OrthopSurg. 2010;18(9):528–36.

36. Danino B, Rödl R, Herzenberg JE, Shabtai L, Grill F,Narayanan U, et al. Guided growth: preliminary resultsof a multinational study of 967 physes in 537 patients.JChildOrthop. 2018;12(1):91–6.

37. Sharkey MS, Grunseich K, Carpenter TO. Contempo-rary medical and surgical management of X-linkedhypophosphatemic rickets. J Am Acad Orthop Surg.2015;23(7):433–42.

38. Horn A, Wright J, Bockenhauer D, Van’t Hoff W, East-wood DM. The orthopaedic management of lower limbdeformity in hypophosphataemic rickets. J Child Orthop.2017;11(4):298–305.

39. Masquijo JJ, FirthGB, SepúlvedaD. Failureof tensionbandplating. JPediatrOrthopB.2017;26(5):449–53.

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