Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients.

Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation.

Bone Material Properties in Bone Diseases Affecting Children.

PURPOSE OF REVIEW: Metabolic and genetic bone disorders affect not only bone mass but often also the bone material, including degree of mineralization, matrix organization, and lacunar porosity. The quality of juvenile bone is moreover highly influenced by skeletal growth. This review aims to provide a compact summary of the present knowledge on the complex interplay between bone modeling and remodeling during skeletal growth and to alert the reader to the complexity of bone tissue characteristics in children with bone disorders. RECENT FINDINGS: We describe cellular events together with the characteristics of the different tissues and organic matrix organization (cartilage, woven and lamellar bone) occurring during linear growth. Subsequently, we present typical alterations thereof in disorders leading to over-mineralized bone matrix compared to those associated with low or normal mineral content based on bone biopsy studies. Growth spurts or growth retardation might amplify or mask disease-related alterations in bone material, which makes the interpretation of bone tissue findings in children complex and challenging.

Dissociation of clinical, laboratory, and bone biopsy findings in adult X-linked hypophosphatemia: a case report.

X­linked hypophosphatemia (XLH) is a phosphate wasting disorder. Typical serum constellations include low serum phosphate as well as high alkaline phosphatase (ALP) and fibroblast growth factor 23 (FGF-23 ) levels. Adult XLH patients usually suffer from (pseudo)fractures, enthesopathies, impaired mobility, and osteoarthritis. We report the case of a middle-aged woman with clinically mild disease, relatively balanced laboratory values, but bone non-healing of the femur post-surgery. Transiliac bone biopsy revealed pronounced osteomalacia and severe deterioration of bone microstructure. Due to the lack of XLH-typical symptoms, the patient was not substituted with calcitriol and phosphate in adulthood. Thus, laboratory findings and radiological examinations do not necessarily reflect bone metabolism in XLH. Bone biopsies should be considered in unclear cases or prior to surgery in adults with XLH.

Bone and growth: basic principles behind rare disorders.

The heterogeneity of "rare bone disorders" can be explained by the number of molecules and regulatory pathways which are responsible for bone health and normal stature. In this article, the most important basic principles behind bone homeostasis from development to structure and regulation of the growing skeleton are summarized. The aim is to provide the reader with some theoretical background to understand the nature of the different main groups of disorders affecting bone stability, longitudinal growth and disturbances of calcium and phosphate homeostasis.

Elevation of phosphate levels impairs skeletal myoblast differentiation.

Hyperphosphatemic conditions such as chronic kidney disease are associated with severe muscle wasting and impaired life quality. While regeneration of muscle tissue is known to be reliant on recruitment of myogenic progenitor cells, the effects of elevated phosphate loads on this process have not been investigated in detail so far. This study aims to clarify the direct effects of hyperphosphatemic conditions on skeletal myoblast differentiation in a murine in vitro model. C2C12 murine muscle progenitor cells were supplemented with phosphate concentrations resembling moderate to severe hyperphosphatemia (1.4-2.9 mmol/l). Phosphate-induced effects were quantified by RT-PCR and immunoblotting. Immunohistochemistry was performed to count nuclear positive cells under treatment. Cell viability and metabolic activity were assessed by XTT and BrdU incorporation assays. Inorganic phosphate directly induced ERK-phosphorylation in pre-differentiated C2C12 myoblast cells. While phosphate concentrations resembling the upper normal range significantly reduced Myogenin expression (- 22.5%, p = 0.015), severe hyperphosphatemic conditions further impaired differentiation (Myogenin - 61.0%, p < 0.0001; MyoD - 51.0%; p < 0.0001). Analogue effects were found on the protein level (Myogenin - 42.0%, p = 0.004; MyoD - 25.7%, p = 0.002). ERK inhibition strongly attenuated phosphate-induced effects on Myogenin expression (p = 0.002). Metabolic activity was unaffected by the treatments. Our data point to a phosphate-induced inhibition of myoblast differentiation without effects on cell viability. Serum phosphate levels as low as the upper normal serum range significantly impaired marker gene expression in vitro. Investigation of cellular effects of hyperphosphatemia may help to better define serum cutoffs and modify existing treatment approaches of phosphate binders, especially in patients at risk of sarcopenia.

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

X­linked hypophosphatemic rickets (XLH, OMIM #307800) is a rare genetic metabolic disorder caused by dysregulation of fibroblast-like growth factor 23 (FGF23) leading to profound reduction in renal phosphate reabsorption. Impaired growth, severe rickets and complex skeletal deformities are direct consequences of hypophosphatemia representing major symptoms of XLH during childhood. In adults, secondary complications including early development of osteoarthritis substantially impair quality of life and cause significant clinical burden. With the global approval of the monoclonal FGF23 antibody burosumab, a targeted treatment with promising results in phase III studies is available for children with XLH. Nevertheless, complete phenotypic rescue is rarely achieved and remaining multisystemic symptoms demand multidisciplinary specialist care. Coordination of patient management within the major medical disciplines is a mainstay to optimize treatment and reduce disease burden. This review aims to depict different perspectives in XLH patient care in the setting of a multidisciplinary centre of expertise for rare bone diseases.

c-Raf promotes angiogenesis during normal growth plate maturation.

Extracellular phosphate plays a key role in growth plate maturation by inducing Erk1/2 (Mapk3/1) phosphorylation, leading to hypertrophic chondrocyte apoptosis. The Raf kinases induce Mek1/2 (Map2k1/2) and Erk1/2 phosphorylation; however, a role for Raf kinases in endochondral bone formation has not been identified. Ablation of both A-Raf (Araf) and B-Raf (Braf) in chondrocytes does not alter growth plate maturation. Because c-Raf (Raf1) phosphorylation is increased by extracellular phosphate and c-Raf is the predominant isoform expressed in hypertrophic chondrocytes, chondrocyte-specific c-Raf knockout mice (c-Raf(f/f);ColII-Cre(+)) were generated to define a role for c-Raf in growth plate maturation. In vivo studies demonstrated that loss of c-Raf in chondrocytes leads to expansion of the hypertrophic layer of the growth plate, with decreased phospho-Erk1/2 immunoreactivity and impaired hypertrophic chondrocyte apoptosis. However, cultured hypertrophic chondrocytes from these mice did not exhibit impairment of phosphate-induced Erk1/2 phosphorylation. Studies performed to reconcile the discrepancy between the in vitro and in vivo hypertrophic chondrocyte phenotypes revealed normal chondrocyte differentiation in c-Raf(f/f);ColII-Cre(+) mice and lack of compensatory increase in the expression of A-Raf and B-Raf. However, VEGF (Vegfa) immunoreactivity in the hypertrophic chondrocytes of c-Raf(f/f);ColII-Cre(+) mice was significantly reduced, associated with increased ubiquitylation of VEGF protein. Thus, c-Raf plays an important role in growth plate maturation by regulating vascular invasion, which is crucial for replacement of terminally differentiated hypertrophic chondrocytes by bone.

Accelerated Linear Growth during Erdafitinib Treatment: An FGFR-Related, but Growth Factor and Sex Steroid-Independent Mechanism?

INTRODUCTION: Growth acceleration during postnatal growth only occurs during puberty as a physiological event and during catch-up growth mediated by growth-promoting therapies in growth disorders. Here we report on novel observations of skeletal symptoms during treatment with erdafitinib, a tyrosine kinase inhibitor (TKI) prescribed on the basis of a compassionate-use program. METHODS: Analysis of anthropometric, biochemical, clinical, and radiographic data of patients with CNS tumors who revealed an unanticipated growth spurt with initiation of therapy with erdafitinib was performed retrospectively. RESULTS: Linear growth acceleration was independent of sex steroids and IGF1 levels, which is especially remarkable in the context of heavily pretreated pediatric neuro-oncology patients with severe growth impairment before initiation of therapy. Growth acceleration was accompanied by a distinct widening of the growth plate and enhanced metaphyseal mineralization shortly after the start of TKI therapy. CONCLUSIONS: While targeted therapies including TKIs have become an essential part of adult cancer treatment, applications in children are still limited. Off-target effects specific to the pediatric population have been observed in various organ systems; however, knowledge about the effect of TKIs on the growing skeleton is scarce. Treatment with erdafitinib inhibits FGFR3-mediated effects and thus represents a very logical hypothetical framework of growth factor and sex steroid-independent growth acceleration.

Health-related quality of life and fatigue in adult rare bone disease patients: A cross-sectional study from Austria.

OBJECTIVES: To assess physical and mental health domains of health related quality of life (HRQoL) as well as fatigue in rare bone disease (RBD) patients and to compare to patients with osteoporosis (OPO) and healthy controls (CTRL) without known bone diseases and to study associations of Fatique Severity Scale (FSS) with eight domains of HRQoL. METHODS: Monocentric, cross-sectional study carried out between 2020 and 2022 in a hospital affiliated with the Vienna Bone and Growth Center (European Reference Network Center for Rare Bone Disease) in Vienna, Austria. The study comprised three types of RBD: Osteogenesis imperfecta, Hypophosphatasia and X-linked Hypophosphatemia. Fatigue was assessed by FSS. The higher score indicates more fatigue severity. HRQoL was assessed by Short-Form Health Survey (SF-36 v2). Physical component (PCS) and mental component summary scores (MCS) were calculated and normalised to a general population. A higher score indicates better HRQoL. Age-adjusted ANCOVA was used to assess differences in PCS and MCS between groups. Spearman correlation was used for associations of FSS with eight domains of HRQoL. RESULTS: Study comprised 50 RBD patients [Mean age (SD) 48.8 (±15.9), 26 % male], 51 OPO patients [66.6 (±10.0), 9.8 % male] and 52 controls [50.8 (±16.3), 26.9 % male]. RBD patients had significantly higher mean age-adjusted FSS (3.5, 95 % CI 3.1-4.0) than controls (2.6, 95 % CI 2.2-3.0, p = 0.008), but not in comparison to osteoporotic patients 2.6 (95 % CI 2.2-3.0, p = 0.69). Diminished age-adjusted PCS of HRQoL was observed in RBD patients with a mean score of 37.1 (95 % CI 33.4-40.8), whereas their MCS of 50.1 (95 % CI 46.6-53.7) was comparable to controls (52.9, 95 % CI 49.8-56.0) and osteoporotic patients (50.2, 95 % CI 45.4-54.9). FSS score was negatively correlated with physical and mental component in RBD (ρ = -0.37, p < 0.05 and ρ = -0.54, p < 0.01, respectively) and OPO patients (ρ = -0.37, p < 0.05 and ρ = -0.35, p < 0.01, respectively). CONCLUSIONS: The HRQoL in adult patients with rare bone diseases is lower than compared to osteoporotic and control group in this Austrian population. Fatigue has significant negative impact on HRQoL and it is important to address it when meeting with RBD patients in clinical practice.

Growth Hormone Therapy: Comparison of Short- and Long-Term Outcomes between Children with Growth Hormone Deficiency and Small for Gestational Age.

INTRODUCTION: Direct comparisons of both short-term and long-term auxological outcomes of growth hormone therapy (GHT) between growth hormone deficiency (GHD) and small for gestational age (SGA) are scarce. METHODS: One hundred three patients with GHD and 53 patients with SGA treated at our tertiary center were investigated. Short-term and long-term outcomes were compared between these groups using multivariable linear regression models with adjustment for age, sex, and height at therapy start, also allowing for sex-specific group comparisons. RESULTS: Mean delta height standard deviation scores (SDS) after 1 year of treatment were significantly higher in GHD (0.90, CI: 0.82-0.99) compared to SGA (0.67, CI: 0.54-0.79) (p = 0.003) with no sex difference. As expected, the mean increase in height SDS at final height (FH) was significantly higher in GHD (2.21, CI: 2.00-2.42) compared to SGA (1.05, CI: 0.75-1.35) (p < 0.001), leading to a target height corrected FH of -0.39 SDS (CI: -0.62 to -0.15) in GHD and -1.22 SDS (CI: -1.57 to -0.87) in SGA (p < 0.001). Girls with GHD had a better long-term outcome, as did boys with SGA when compared to the respective opposite sex. The cut-off of delta height of 0.5 SDS during the first year had a low sensitivity to detect long-term non-responders. We found a relation between short-term and long-term outcomes in GHD but not in SGA (adjusted R2 = 0.66 vs. 0.01). CONCLUSION: In contrast to GHD, we observed practically no relationship between 1st-year and long-term outcomes in SGA patients treated with GH.

Clinical, Radiographic, and Biomechanical Evaluation of the Upper Extremity in Patients with Osteogenesis Imperfecta.

Introduction: Osteogenesis imperfecta (OI) is a hereditary disorder primarily caused by mutations in type I collagen genes, resulting in bone fragility, deformities, and functional limitations. Studies on upper extremity deformities and associated functional impairments in OI are limited. This cross-sectional study aimed to evaluate upper extremity deformities and functional outcomes in OI. Methods: We included patients regardless of their OI subtypes with a minimum age of 7 years. Radiographic analysis of radial head dislocation, ossification of the interosseous membrane, and/or radioulnar synostosis of the forearm were performed, and deformity was categorized as mild, moderate, or severe. Clinical evaluation was performed using the Quick Disabilities of Arm, Shoulder, and Hand (qDASH) questionnaire and shoulder-elbow-wrist range of motion (ROM). Three-dimensional motion analysis of the upper limb was conducted using the Southampton Hand Assessment Procedure (SHAP). The SHAP quantifies execution time through the Linear Index of Function (LIF) and assesses the underlying joint kinematics using the Arm Profile Score (APS). Additionally, the maximum active Range of Motion (aRoM) was measured. Results: Fourteen patients aged 8 to 73 were included. Radiographic findings revealed diverse deformities, including radial head dislocation, interosseous membrane ossification, and radioulnar synostosis. Six patients had mild, six moderate, and two severe deformities of the upper extremity. Severe deformities and radial head dislocation correlated with compromised ROM and worse qDASH scores. The qDASH score ranged from 0 to 37.5 (mean 11.7). APS was increased, and LIF was reduced in OI-affected persons compared with non-affected peers. APS and LIF also varied depending on the severity of bony deformities. aRoM was remarkably reduced for pro-supination. Conclusion: Patients with OI showed variable functional impairment from almost none to severe during daily life activities, mainly depending on the magnitude of deformity in the upper extremity. Larger multicenter studies are needed to confirm the results of this heterogeneous cohort. Level of evidence: Retrospective clinical study; Level IV.

Fibroblast growth factor 23 and Klotho are present in the growth plate.

INTRODUCTION: Regulation of phosphate homeostasis is essential for mineralization and enchondral ossification. Fibroblast growth factor 23 (FGF23) and its obligatory co-receptor Klotho (KL) play a key role in this process by influencing both renal phosphate reabsorption and vitamin D metabolism. In disease, excessive action of FGF23 leads to hypophosphatemic rickets, while its deficiency causes tumoral calcinosis. Although osteocytes and osteoblasts are widely seen as the primary source of FGF23 under physiological conditions, the origin of systemic FGF23 remains controversial. In this study, we investigated the expression of FGF23 and KL in porcine growth plate cartilage, adjacent tissues, and parenchymal tissues. MATERIALS AND METHODS: Tissue samples were obtained from 4- to 6-week-old piglets. mRNA expression was quantified by real-time PCR and normalized to 18S rRNA. Immunohistochemical staining was performed for FGF23, KL, collagen type X, and FGF receptor 1. Growth plate chondrocyte subpopulations were acquired by collagenase digestion of growth plate explants and subsequent density gradient centrifugation. RESULTS: We could detect both FGF23 and KL mRNA and protein in growth plate chondrocytes. FGF23 expression was mainly found in hypertrophic and resting chondrocytes. Furthermore, significant expression of both genes was observed in bone, liver, and spleen. CONCLUSION: These data challenge previous expression analyses, in particular theories of bone as the exclusive source of FGF23. Moreover, significant expression of FGF23 and KL within the growth plate and adjacent tissues imply a potential local role of FGF23 in chondrocyte differentiation and tissue mineralization.

Evaluation of bone mineral density and bone turnover in children on anticoagulation.

Background: Childhood and adolescence are critical periods of bone mineral acquisition. Children on anticoagulation (AC) might have an increased risk for reduced bone mineral density (BMD). Risk factors for impaired bone accumulation include chronic diseases, immobility, and medication. Vitamin K (VK) deficiency reflected by undercarboxylated osteocalcin levels (ucOC) has been identified as a predictor of osteoporosis and fractures. Data on bone health in children under AC are sparse. Aims: To evaluate BMD in children on AC and characterize the risk factors of low BMD, including VK and Vitamin D (VD) status. Methods: Single-center cross-sectional study of clinical, biochemical, and densitometric parameters. Assessment of VK surrogate parameters included ucOC and matrix gla protein (MGP). Results: A total of 39 children (4-18 years; 12 females) receiving AC were included, 31 (79%) on VK antagonists and 8 (21%) on direct oral anticoagulants. Overall, BMD was decreased for both the lumbar spine (LS; -0.7SDS) and total body less head (TBLH; -1.32SDS) compared with pediatric reference data. Significant associations were found between early pubertal development and TBLH-BMD, and between BMI and LS-BMD. VK surrogate parameters were highly related to patients' age and pubertal development. Neither serum parameters nor AC-related factors predicted BMD. VD was detected in 10/39 patients with lower values during puberty. Conclusion: Our data indicate BMD reduction in pediatric patients on AC. Although AC-related factors did not predict reduced BMD, low BMI and pubertal stages represented important risk factors. Awareness of risk factors for low BMD and high prevalence of VD deficiency during puberty could contribute to the improvement of bone health in this vulnerable patient group.

SUCCESSFUL USE OF METYRAPONE SUPPOSITORIES IN AN INFANT WITH NEONATAL CUSHING AND MCCUNE ALBRIGHT SYNDROME- A CASE REPORT.

A female toddler was diagnosed at age ten months with peripheral precocious puberty and hypercortisolism related to McCune Albright Syndrome with additional systemic complications. We present the first successful, long-term use of metyrapone as suppositories, with striking clinical and biochemical improvement and no side-effects.

The ankle in XLH: Reduced motion, power and quality of life.

Background: X-linked hypophosphatemia (OMIM 307800) is a rare bone disease caused by a phosphate-wasting condition with lifelong clinical consequences. Those affected suffer from bone pain, complex skeletal deformities, impaired mobility and a reduced quality of life. Early osteoarthritis and reduced range of motion of the lower limbs are known pathologies in XLH patients. However, XLH-specific data on the affected compartments such as the ankle joint through the evaluation of radiographic and gait analysis data is still lacking. Patients and methods: In this cross-sectional study, patients with genetically verified XLH, age ≥ 16 - 50 years and a complete record of gait analysis and or radiographic analysis data were included. Clinical examination, radiological and gait analysis data were compared to norms using the dataset of our gait laboratory registry. Radiographic analysis included tibial deformity analysis and assessment of osteoarthritis and enthesopathies. Western Ontario and McMaster Universities Arthritis Index (WOMAC), SF36v2, American Orthopedic Foot and Ankle Society score (AOFAS) and the Foot and Ankle Outcome Score (FAOS) were used. Twentythree participants with 46 limbs were eligible for the study. Results: A total of 23 patients (n=46 feet) met the inclusion criteria. Patients with XLH had significantly reduced gait quality, ankle power and plantar flexion (p < 0.001) compared to a historic gait laboratory control group. Ankle valgus deformity was detected in 22 % and ankle varus deformity in 30 % of the patients. The subtalar joint (59.1%) as well as the anterior tibiotalar joint (31.1%) were the main localizations of moderate to severe joint space narrowing. Ankle power was decreased in moderate and severe subtalar joint space narrowing (p < 0.05) compared to normal subtalar joint space narrowing. No lateral or medial ligament instability of the ankle joint was found in clinical examination. Tibial procurvatum deformity led to lower ankle power (p < 0.05). Conclusions: This study showed structural and functional changes of the ankle in patients with XLH. Subtalar ankle osteoarthritis, patient reported outcome scores and clinical ankle restriction resulted in lower gait quality and ankle power.

Lifetime impact of achondroplasia study in Europe (LIAISE): findings from a multinational observational study.

BACKGROUND: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults. METHODS: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes. RESULTS: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes. CONCLUSIONS: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368.

Disorders of the Calcium Sensing Signaling Pathway: From Familial Hypocalciuric Hypercalcemia (FHH) to Life Threatening Conditions in Infancy.

Familial hypocalciuric hypercalcemia (FHH) is a mostly benign condition of elevated calcium and PTH levels based on a hyposensitive calcium sensing receptor (CaSR) in FHH 1 or its downstream regulatory pathway in FHH2 and FHH3. In children, adolescents and young adults with FHH the main challenge is to distinguish the condition from primary hyperparathyroidism and thereby to avoid unnecessary treatments including parathyroidectomy. However, inheritance of FHH may result in neonatal hyperparathyroidism (NHPT) or neonatal severe hyperparathyroidism (NSHPT), conditions with high morbidity, and in the latter even high mortality. This review focuses on the genetic and pathophysiological framework that leads to the severe neonatal form, gives recommendations for counselling and summarizes treatment options.

[Osteogenesis imperfecta : A multidisciplinary challenge]. / Osteogenesis imperfecta : Eine multidisziplinäre Herausforderung.

Osteogenesis imperfecta (OI) describes a group of rare diseases which are associated with an increased tendency to bone fractures. In addition to the main symptom of fractures, OI is characterized by a variety of pediatric, pediatric orthopedic and anesthesiological challenges. The multidisciplinary expertise is mostly concentrated at specialized centers. The current treatment concepts aim at minimizing the fracture rate, prevention and treatment of deformities, pain reduction and improved mobility. In addition to pharmacotherapy, conservative and surgical measures are also applied. Scheduled interventions on the extremities are one of the most commonly performed operations in children with OI. Various intramedullary nailing techniques are available. This article addresses the important aspects of multidisciplinary care of children with OI concerning the treatment of the lower extremities.

Persistent Lower Limb Deformities Despite Amelioration of Rickets in X-Linked Hypophosphatemia (XLH) - A Prospective Observational Study.

Background: Gait deviations, lower limb pain and joint stiffness represent key symptoms in patients with X-linked hypophosphatemia (XLH, OMIM 307800), a rare disorder of mineral homeostasis. While the pathomechanism for rickets is well understood, the direct role of PHEX (Phosphate-regulating neutral endopeptidase) deficiency in non-rachitic features including complex deformities, skull and dental affections remains unclear. FGF23-inhibiting antibody treatment can normalize serum phosphate levels and to improve rickets in XLH patients. However, linear growth remains impaired and effects on lower limb deformity and gait are insufficiently studied. Aims: To characterize and evaluate the course of lower limb deformity in a case series of pediatric XLH patients receiving Burosumab therapy. Methods: Comparative assessment of planar radiographs, gait analysis, biochemical and clinical features of pediatric patients before and ≥12 months after initiation of FGF23-inhibiting was performed prospectively. Lower limb maltorsion was quantified by torsional MRI and gait analysis. Standardized deformity analysis of lower limb anteroposterior radiographs was conducted. Results: Seven patients (age 9.0 +/-3.6 years) were eligible for this study. All patients received conventional treatment before onset of antibody treatment. Maltorsion of the femur was observed in 8/14 legs using torsional MRI (mean antetorsion 8.79°). Maltorsion of the tibia was observed in 9/14 legs (mean external torsion 2.8°). Gait analysis confirmed MRI findings with femoral external malrotation prior to and one year after onset of Burosumab therapy. Internal foot progression (intoeing gait) remained pathological in all cases (mean 2.2°). Knee rotation was pathologically internal 10/14 legs. Mean mechanical axis deviation (MAD) of 16.1mm prior to Burosumab changed in average by 3.9mm. Three children underwent guided growth procedures within the observation period. Mild postprocedural rebound of frontal axis deviation was observed under Burosumab treatment in one patient. Conclusions: This is the first study to investigate lower limb deformity parameters quantitatively in children with XLH receiving Burosumab. One year of Burosumab therapy was associated with persistent maltorsion and frontal axis deviation (varus/valgus) despite improved rickets in this small, prospective uncontrolled study.