Craniosynostosis in Children with X-Linked Hypophosphatemia Treated with Burosumab: Insights from a Single Center Cross-sectional Cohort Screening

Craniosynostosis in Children with X-Linked Hypophosphatemia Treated with Burosumab: Insights from a Single Center Cross-sectional Cohort Screening | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Craniosynostosis in Children with X-Linked Hypophosphatemia Treated with Burosumab: Insights from a Single Center Cross-sectional Cohort Screening Francesca Aiello, Francesca Romano, Adalgisa Festa, Giampiero Baroncelli, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8107500/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background X-linked hypophosphatemic rickets (XLH) is the most common genetic form of hypophosphatemia, caused by elevated FGF23 and renal phosphate wasting. Cranial anomalies such as craniosynostosis (CS) and Chiari type I malformation (CM-I) are reported in XLH, but prevalence data—especially in the context of burosumab therapy—remain limited. This monocentric study evaluated (a) the prevalence and predictors of CS and CM-I in children with XLH receiving burosumab, and (b) the utility of brain black bone MRI as a nonionizing alternative to computed tomography (CT). Methods Twelve children (8.3 ± 4.6 years; four males) were assessed after a mean burosumab treatment duration of 28 ± 14.6 months. All were asymptomatic or paucisymptomatic for CS. Cranial morphology was evaluated via CT, and MRI was performed in patients with CS; three children without CS underwent MRI with black bone sequences. Results CS with sagittal suture fusion was present in 41.7% of patients, and CM-I in 25%. No patient had a normal cranial index(>80%).CS correlated significantly with male sex(p < 0.01), dolichocephaly(p < 0.001), and CM-I(p < 0.01). black bone sequences MRI successfully visualized sutures in children without CS. Burosumab improved phosphate metabolism and rickets, but showed no association with CS prevalence. Conclusions Sagittal suture fusion and CM-I are common in XLH, with male sex and dolichocephaly identified as strong predictors of CS. These findings underscore the importance of radiological screening in XLH and support MRI with black bone sequences as a promising diagnostic tool. Arnold-Chiari Malformation Black Bone MRI Burosumab Cephalic Index Craniosynostosis Dolicocephaly Hypophosphatemic Rickets Neuroradiography X-Linked Dominant Figures Figure 1 Figure 2 Figure 3 Figure 4 Highlights CS was common in a cohort of XLH children(41.7%), mostly involving sagittal fusion. Dolicocephaly and male sex were associated with CS. Chiari malformation type 1 was common in CS patients. Age and dose at burosumab start did not differ between CS and non-CS patients. Black bone MRI is a valuable radiation-free imaging option for studying suture patency. 1. Background X-linked hypophosphatemic rickets (XLH) is a rare hereditary disorder caused by mutations in the PHEX gene. It is characterized by elevated levels of fibroblast growth factor 23 (FGF23), wasting of renal phosphate, and active rickets. The incidence of XLH is estimated at 3.9 per 100,000 live births, with a prevalence ranging from 1.7 to 4.8 per 100,000 individuals [1,2]. Currently, XLH is the most common form of rickets in developed countries. The first clinical signs typically appear within the first two years of life, with affected children exhibiting lower extremity deformities and a waddling gait upon reaching walking age, accompanied by bone pain and progressively disproportionate short stature [3, 4, 5]. Over time, dental hypomineralization increases the risk of tooth abscesses and periodontitis [6]. In adulthood, patients frequently experience hearing loss, pseudofractures due to osteomalacia, osteoarthritis, enthesopathies, and spinal stenosis, all of which contribute to reduced quality of life [7]. Complete or partial ossification of cranial sutures, known as craniosynostosis (CS), is a potential complication of XLH. This altered ossification process causes cranial dysmorphia, reduced intracranial volume, and secondary abnormally high intracranial pressure [8,9]. CS remains an underrecognized manifestation of XLH, with limited research on its prevalence, age of onset, main factors influencing suture fusion, and related symptoms. A recent systematic review estimated a pooled prevalence of 22%, with significant variation among studies due to differences in diagnostic criteria, methodologies, and patient descriptions [10]. Recent evidence-based guidelines from 2025 recommend performing a fundoscopic examination and/or brain imaging only in patients presenting with headache, neck pain, or papilledema [11]. Additionally, most published data on neurosurgical complications preceded the introduction of novel treatment options for XLH. Before 2018, the standard treatment for XLH involved oral phosphate supplementation combined with active vitamin D metabolites. In 2018, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved burosumab, a fully human recombinant IgG1 monoclonal antibody targeting FGF23, for the treatment of XLH in children over one year of age and in adults [12]. To date, no studies have evaluated the impact of burosumab therapy on neurosurgical complications. This observational cross-sectional study aimed to investigate the prevalence of CS and its associated symptoms and complications in a cohort of twelve children with XLH receiving burosumab treatment. Black bone magnetic resonance imaging (MRI) in a subgroup, a radiation-free imaging technique, was used as a secondary method to assess suture patency. 2. Methods This observational, cross-sectional, single-center study was conducted on a pediatric population of twelve children with XLH who were followed at the Endocrinology Service of the Department of Woman, Child, General, and Specialized Surgery at the University of Campania “Luigi Vanvitelli,” Naples. All neurosurgical evaluations were performed by the Craniofacial Unit of the Neurosurgical Department at Santobono Children's Hospital, Naples, Italy, which is an integral part of our multidisciplinary team for neurosurgical assessment and patient management. The study was approved by the Ethics Committee of the University of Campania “Luigi Vanvitelli.” In accordance with the World Medical Association Declaration of Helsinki, written informed consent was obtained from parents, and oral assent was collected from all participants. Patients were enrolled for neuroradiological evaluation between January 1, 2023, and May 31, 2024. 2.1 Population and clinical parameters Twelve pediatric patients (four males) with a molecular diagnosis of XLH were recruited for this study. The mean age at diagnosis was 2.5 ± 1.0 years (range: 10 months to 3.5 years). Each patient underwent a comprehensive clinical and neuroradiological assessment. The mean age at neuroradiological examination was 8.3 ± 4.6 years. The following anthropometric parameters were recorded at the time of evaluation: height, growth velocity, weight, pubertal stage, and head circumference. Measurements were performed via standardized equipment: a Wunder Sa. BI scale for weight and a HILTI PD30 digital altimeter for height. To minimize measurement bias, each parameter was assessed three times. Cacciari growth curves stratified by sex and age were used for the standardization of the anthropometric assessments [13]. At the time of neuroradiological evaluation, the following biochemical parameters were collected for each patient: serum calcium, phosphate, creatinine, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH) 2 D), alkaline phosphatase (ALP), bone isoenzyme of alkaline phosphatase (BALP), and urinary excretion of calcium, phosphate, and creatinine. All laboratory analyses were conducted at the central laboratory of A.O.U. “L. Vanvitelli”. Serum 25OHD, 1,25(OH) 2 D, and PTH levels were measured via the CLIA DiaSorin® immunoassay method, whereas serum electrolytes, creatinine, and ALP and BALP were analyzed via the Architect immunoassay (Abbott kit®). The TmP/GFR was assessed via the method of Stark et al. [14]. The Rickets Severity Score (RSS) was determined at the time of neuroradiological evaluation on the basis of wrist and knee X-ray scans. Scoring was performed by a single orthopedic specialist with expertise in metabolic bone disorders. The total RSS was calculated as the sum of the wrist score (ranging from 0 to 4) and the knee score (ranging from 0 to 6), with higher scores indicating more severe manifestations of rickets [15]. Medical records were reviewed to retrieve anthropometric and clinical data prior to the initiation of burosumab therapy. 2.2 Neuroradiological evaluation Figure 1 illustrates the neuroradiological assessment procedures of the patients in our cohort. Briefly, neuroradiological evaluation was offered to all patients who were able to undergo a complete brain computed tomography (CT) scan, even in the absence of neurological symptoms. MRI was performed in all patients with craniosynostosis and in three patients without craniosynostosis. All skull CT scans were performed at the Neuroradiology Unit of A.O.U. “Luigi Vanvitelli,” whereas MRIs were conducted either at the same institution or at the Neuroradiology Unit of Santobono Pausilipon Children’s Hospital in cases requiring sedation (four patients). Individuals diagnosed with CS were subjected to an extensive neurological assessment encompassing funduscopic examination, cranial nerve evaluation, tests of coordination and balance, and recording of somatosensory and motor evoked potentials. 2.2.1 TC scans Three-dimensional rendering of skull CT scans was performed to evaluate suture patency. Sagittal section multiplanar reconstruction (MPR) allows the calculation of the cranial index (CI) and skull base angle (sellar-basion-nasion angle). The CI was expressed as the percentage ratio of transverse-to-anteroposterior diameters. A CI <75% was diagnostic for dolichocephaly, whereas a CI between 75% and 80% indicated mesocephaly [16]. Platybasia, characterized by abnormal flattening of the skull base, was assessed via the Welcher basal angle, which is formed at the intersection of lines drawn from the nasion to the tuberculum sella and from the basion to the tuberculum. The average Welcher basal angle is 132° and is considered normal when 140° [17]. The position of the cerebellar tonsils in sagittal sections was evaluated for the diagnosis of Chiari type I malformation (CM-I), which is defined as the descent of the cerebellar tonsils >5 mm through the foramen magnum as identified by the basion-opistion line[18]. 2.2.2 Brain MRI All patients with CS underwent brain MRI to assess brain morphology via T1, T2, and FLAIR sequences. Additionally, angio-MRI with 3D time-of-flight (TOF) sequencing was performed in two patients. Four patients underwent MRI under general anesthesia. To evaluate whether brain MRI resolution could effectively detect suture patency, three patients without CS who did not require sedation underwent MRI with black bone sequencing at the Neuroimaging Research Center of A.O.U. “Luigi Vanvitelli”. A 3-Tesla MRI with black bone sequences provided a low flip angle, gradient echo (GRE) MRI sequence, yielding high image contrast between the bone and surrounding tissues. Images were acquired in the axial plane via a three-dimensional GRE sequence. The flip angle was incrementally reduced from 60° to 5° while maintaining a short echo time (4.2 ms) and repetition time (8.6 ms). The remaining scanning parameters are detailed in supplemental Table 1. Fig. 1 Flowdiagram of neuroradiological evaluation [ Insert figure 1] 2.3 Statistical analysis The data were analyzed via SPSS 28.0 software (International Business Machines Corporation). Descriptive statistics were applied to characterize the whole cohort, and the data are presented as frequencies or means and standard deviations (SDs) as appropriate. Lilliefors’ test was run to investigate the normal distribution: nonparametric data were analyzed via the Mann‒Whitney U test, whereas a two-tailed Student’s t test was performed for parametric analysis. For correlation analysis, a Pearson correlation coefficient was calculated. Statistical significance was set at p < 0.05. 3. Results 3.1 Patients Table 1 summarizes the clinical and biochemical findings of the entire cohort before burosumab treatment and at the time of neuroradiological evaluation. Each patient received conventional therapy with oral phosphate supplements and active vitamin D metabolites since diagnosis for a mean period of 36.2±35 months (median 24.9 months, range: 4.0–88.1) before starting burosumab. All patients demonstrated good treatment adherence, except for three patients (Pt 2, 8 and 12). The final mean elemental phosphorus dose before discontinuation was 41.3±23 mg/kg body weight (range: 20–80) divided into 4 daily doses associated with alfacalcidiol (mean dose 33±2.2 ng/kg/daily) or calcitriol (3 patients, mean dose 21 ng/kg/daily). None of the patients exhibited nephrocalcinosis or secondary/tertiary hyperparathyroidism while receiving oral phosphate supplements or active vitamin D metabolite therapy. At the time of neuroradiological assessment, all patients were receiving burosumab for a mean duration of 27.6 ± 14.6 years (range 9–44). The starting dose of burosumab was 0.48±0.04 mg/kg/14 days and was tailored to 1.53±0.45 (range 0.8–2) at the time of neuroradiological evaluation. All patients demonstrated significant increases in their serum phosphate (p=0.02) and 1,25(OH) 2 D levels (p=0.04) and TmP/GFR values (p=0.04). ALP and BALP levels were significantly lower in all patients (p<0.001). The RSS improved during burosumab treatment (p=0.02) (Table 1). Circulating PTH levels, as well as serum calcium and calcium excretion, did not significantly change throughout treatment (data not shown). No adverse events related to burosumab treatment were observed in any patient. None of the patients developed hypercalcemia, hyperphosphatemia, nephrocalcinosis, or cardiac abnormalities throughout the treatment period. The results of general neurological examinations were within normal limits for all patients. No patient exhibited frank macrocephaly; however, 10 out of 12 patients demonstrated relative macrocephaly, defined as a head circumference measurement exceeding 2 SDSs above the individual's body size or other physical parameters. Headache was reported in four patients (Table 1). [insert table 1] 3.2 Neuroradiological characterization CT scan analysis revealed that 41.7% of patients (four males and one female) presented with CS together with a remarkably altered CI below 75%. Patient 1 exhibited complete fusion of the sagittal suture and partial closure of the coronal suture (see Figure 2 ). Patients 2, 3, and 4 presented with isolated complete sagittal suture fusion. Patient 5 had partial sagittal suture fusion. None of the patients presented with pansynostosis. Fig. 2 3D CT Skull Reconstruction in a Patient with XLH- associated craniosynostosis [ Insert figure 2] The arrow in panel A indicates complete fusion of the sagittal suture, while the arrow in panel B highlights partial closure of the coronal suture No patient had a normal CI (>80%); altered skull morphology was observed in all patients, with seven patients without CS presenting mesocephaly and five patients with CS presenting dolichocephaly. An altered basal skull angle indicating platybasia was identified in one patient, with concurrent CM-I. For further details, refer to Table 2 . [insert table 2] MRI revealed CM-I in three patients with CS (Patients 1, 2, and 4), corresponding to a prevalence of 25% in the whole cohort and 60% in patients with CS. A statistically significant association was observed between CM-I and CS (p = 0.009, χ² test). Angio-MRI in Patient 4 revealed optic nerve sheath ectasia and the absence of blood flow in both transverse sinuses, accompanied by parieto-occipital collateral compensatory circulation (see Figure 3). Figure 3. Brain MRI Showing Arnold-Chiari Type I Malformation in a Patient with XLH [insert figure 3] A) Sagittal brain MR image: Hindbrain herniation is evident with cerebellar tonsil protrusion through the foramen magnum, identified by the basion-opistion line ( red line) . Note the dolicocephalic shape of the cranial vault. B) Axial brain MR image: Optic nerve sheath ectasia ( red arrow ). C) 3D-TOF sequences in coronal view: Absence of a flow signal in the transverse venous sinuses ( white arrows ) D) 3D-TOF sequences in sagittal view: collateral circulation ( yellow arrow ) The black bone RMI sequence, which was performed in three patients without CS to confirm the efficacy of this technique for visualizing cranial sutures, clearly showed suture patency, confirming the TC results. (see Figure 4). Figure 4. Black Bone MRI sequence in the axial plane at the level of the bregma in Patient 11. [Insert figure 4] The image highlights the coronal sutures (indicated by the red arrow) and the sagittal suture (indicated by the yellow arrow). 3.3 Characteristics of patients with CS vs patients without CS CS was significantly associated with male sex (p = 0.0135, χ² test). Compared with patients without craniosynostosis (NO-CS), patients with CS presented a significantly greater head circumference SDS at the start of burosumab therapy (p = 0.015). This trend of increased head circumference persisted later in life during neuroradiological evaluation but did not reach statistical significance. CI was significantly lower in patients with CS (CI = 70.1 ± 2.5%) than in those without CS (CI = 78.4 ± 1.8%, p <0.001). However, all patients exhibited skull shape alterations, including those without CS. The prevalence of headache was significantly greater in the CS group (p = 0.02); however, two patients with CS remained asymptomatic for headache, one of whom had associated CM1. No significant difference was found in the number of dental abscesses or the presence of hearing impairment between the two groups. No significant differences were observed in the age at initiation of burosumab therapy (p = 0.78). The duration of treatment was comparable between the groups, with a mean treatment period of 25.2 ± 17.5 months (range 0.6–11.0) in the CS group and 29.3 ± 10.4 months (range 0.3–7.3) in the NO-CS group (p = 0.45). No differences were found in the mean burosumab dosage (p = 0.68). Subgroup analysis comparing patients with and without CS did not reveal any significant biochemical differences in calcium‒phosphate biochemical parameters before or after burosumab treatment (data not shown), except for a greater RSS at neuroradiological evaluation (p = 0.030) in patients with CS. CM-I was significantly associated with CS (p = 0.025). All the parameters analyzed for the subgroups are reported in Supplementary Table 2. Funduscopic examination ruled out papilloedema in all patients with CS. Cranial nerve assessments confirmed normal visual acuity, pupillary reactions, facial symmetry, and hearing in all patients. The coordination and balance were preserved. Motor and sensory evaluations, including evoked motor and sensory potentials, ruled out focal neurological deficits in all patients. At present, no patient has met the criteria for surgical decompression or cranial hypertension intervention. 4. Discussion This observational, cross-sectional study is the first to systematically examine patients with XLH while receiving burosumab therapy for CS, even in the absence of neurological symptoms. As expected, in our cohort, burosumab therapy improved phosphate metabolism and rickets severity, indicating both effectiveness and safety in a real-world clinical setting. Furthermore, our analysis revealed a 41.7% incidence of CS, all involving sagittal suture fusion, with one case also showing partial coronal suture closure. This rate exceeds the 22% pooled prevalence reported by Fisch et al. [10], indicating heterogeneity among studies. Previous studies by Rothenbuhler et al. [20] and Arenas et al. [21] reported elevated rates of CS (67% and 52%, respectively). In particular, our data align with those of Arenas et al., who analyzed a cohort of both symptomatic and asymptomatic patients, similar to our study. Compared with the general pediatric population, in which CS may occur in ~1 per 2,100–2,500 births [22], XLH patients have a markedly increased risk of CS. The variability in reported prevalence may be due to differences in study design. Unlike retrospective reports, our study prospectively screened genetically confirmed XLH patients, avoiding diagnostic bias. With respect to the type of CS, sagittal suture involvement was present in all affected individuals in our cohort. Fisch et al. [10] reported that sagittal synostosis was present in 42% to 100% of patients with XLH and CS, unlike patients with idiopathic CS, where sagittal fusion appeared in 40%-78% of patients [23]. The median age at evaluation of our patients was 8.3 years; however, no definitive information can be provided regarding the average age of CS onset. A recent literature review by Munns et al. [24] reported a median age of diagnosis of approximately 2 years, in which patients were referred for neurosurgical evaluation due to symptoms or clinical signs of CS [8, 24, 25]. Our study revealed that the evolution of the CS in XLH patients can be silent and insidious, as 2 of our 5 CS patients did not present with headache or neurological signs. Interestingly, morphological skull assessment revealed shape alterations in all our patients: dolichocephaly in all CS patients and mesocephaly in all the other patients. Moreover, relative macrocephaly, defined by head circumference >2 SDs above the height percentile, was identified in all CS patients. Before burosumab treatment, individuals affected by CS had significantly greater head circumferences, although the differences were not statistically significant at the neuroradiological evaluation. However, we cannot determine whether this difference could be attributable to the effect of burosumab on skull shape. These findings emphasize the value of head circumference monitoring and careful head shape observation in XLH patients to perform early imaging; however, skull morphology is not sufficient to identify patients with CS. A statistically significant correlation of CS with male sex was found despite XLH being more common in females. In the meta-analysis by Fisch et al. [10], sex prevalence was available in 4 out of 10 studies analyzed, with reported male prevalence rates ranging from 46% [8] to 100% [26]. Experimental models support this sex bias: male Hyp mice display more severe craniofacial abnormalities [27]. The protective effect of the unaffected PHEX allele in heterozygous females may partially explain this trend [28]. Male predominance has also been noted in nonsyndromic CS [29, 30], likely due to sex-related hormonal and transcriptional effects on osteogenesis [31,32]. These findings suggest that male sex itself may be associated with greater phosphate metabolism imbalance, contributing to CS susceptibility. CS was associated with a higher RSS and a trend toward higher ALP levels during burosumab treatment, suggesting a possible link to more severe disease or less responsiveness to treatment. No associations were found between burosumab initiation age, treatment duration, and CS occurrence. Owing to the small sample size and the lack of neuroradiological investigations before starting burosumab, no conclusions regarding the impact of burosumab on suture closure can be drawn. However, two of the five patients diagnosed with CS started burosumab therapy within the first two years of life. This may suggest that the cellular mechanisms underlying CS due to phosphate metabolism dysregulation are established at an even earlier developmental stage. Preclinical data from Hyp mice indicate that suture abnormalities appear by three weeks of age [33], with heightened expression of FGFR1/FGFR2 observed even before birth [34]. These findings support FGF/FGFR signaling as a driver of CS, potentially through the upregulation of FGF23 [34, 35]. Such mechanisms may explain early and frequent suture pathology in XLH and require further investigation. CM-I was present in 60% of XLH patients with CS, reinforcing a link between suture fusion and posterior fossa dynamics, as reported by Caldemeyer et al. [36] and Rothenbuhler et al. [20]. The strong association between CM-I and sagittal synostosis suggested that cerebellar descent may result from decreased cranial compliance during brain growth, a phenomenon underrecognized in isolated scaphocephaly. This distinction implies different natural histories in XLH, challenging the extrapolation of natural history, prognosis, and surgical indications from isolated conditions to XLH. Not all patients with CM-I presented headache; therefore, this symptom cannot be reliable for deciding which patient to screen. Nevertheless, in children with XLH receiving conventional treatment or burosumab, in the presence of CS or skull shape malformation, headache, neurological symptoms or visual disturbances, or suspected spinal stenosis on the basis of clinical symptoms, brain/spine MRI has been suggested [37]. None of our patients required surgical intervention. The specific indications for surgical intervention in XLH patients remain unclear. Twenty-one cases of children with XLH and CS who underwent neurosurgery have been reported thus far [9, 20, 36-49] (Supplemental Table 3). The median age at neurosurgical referral in these reports was 3 years, and the mean age at surgery was 4 years. Sagittal suture fusion was the most frequent abnormality (16 patients). Combined suture fusion occurred in three patients; the suture type was unspecified in two patients. Most patients exhibited signs of cranial hypertension; eight had subclinical intracranial pressure elevation. Strabismus emerged as a key sign of increased ICP in three patients. CM-I was reported in four children. Owing to the older age at diagnosis and treatment, the most common surgical technique was cranial vault remodeling (9 patients), followed by craniectomy (5 patients) and parietal plastic surgery (2 patients). Four papers did not report the procedure. The outcomes were favorable, with no reinterventions during a median follow-up of 21 months (range: 6–60 months). However, outcome data were lacking for over half of the patients. Despite the high prevalence of CS, the need for surgery in XLH patients is lower than that in patients with isolated CS, likely due to delayed diagnosis and milder clinical presentation. Late surgery may impair optimal aesthetic outcomes. Therefore, surgery is probably reserved for patients with intracranial hypertension in the XLH setting. Finally, black bone MRI, performed in three of our patients, demonstrated high reliability in assessing cranial suture patency. While CT remains the diagnostic gold standard for assessing CS due to its high-resolution bone imaging ability and 3D rendering capability, it involves ionizing radiation exposure. To mitigate this, low-dose CT has gained traction, as shown by Montoya et al. [51]; however, its limited soft-tissue resolution hinders the detection of intracranial anomalies. In recent years, MRI of the cranial vault has become increasingly valuable, particularly in pediatric populations [52] requiring repeated imaging. MRI avoids ionizing radiation and offers superior visualization of complications such as hydrocephalus and tonsillar herniation. Black bone MR sequences provide detailed imaging of both cranial sutures and associated anomalies, including CM-I [53]. Our study has several limitations, including the small cohort and the lack of data on the age at onset of CS or cerebellar descent. Furthermore, owing to the study design, no definite data regarding the potential efficacy of burosumab for treating CS can be inferred. Nonetheless, our results reported the prevalence of CS in a cohort of asymptomatic or paucisymptomatic children with XLH, some of whom started burosumab at quite an early age. These findings indicate the utility of neuroradiological screening in XLH patients, particularly in males, where a low CI may be the only indicator of CS, even in the presence of associated CM-I. Brain MR images, specifically black bone sequences, represent a promising, nonionizing alternative to CT scans for screening CM-I associated with CS. 5. Conclusion This study provides the first comprehensive neuroradiological screening of CS in children with XLH undergoing burosumab therapy, reinforcing the hypothesis that CS is a significant and underrecognized feature of XLH. While no clear impact of burosumab on suture closure was identified due to sample size and study limitations, the findings emphasize the need for regular monitoring. Importantly, black bone MRI has emerged as a viable, radiation-free alternative to CT for evaluating suture patency and detecting associated anomalies. Our findings call for proactive surveillance strategies at XLH, and routine neuroimaging and cranial morphometry may support early detection. Future studies should expand investigations into adult XLH patients and evaluate the long-term consequences of skull and cranio-vertebral anomalies. Longitudinal studies are warranted to clarify the natural history of craniosynostosis in XLH and to assess the potential effects of burosumab. Abbreviation 1,25(OH) 2 D : 1,25-dihydroxyvitamin D 25OHD: 25-hydroxyvitamin D ALP: alkaline phosphatase BALP: bone isoenzyme of alkaline phosphatase CI: cranial index CM-I: Chiari type I malformation CS: craniosynostosis CT: computed tomography EMA: European Medicines Agency FDA Food and Drug Administration FGF23: fibroblast growth factor 23 GRE: gradient echo MRI: magnetic resonance imaging PTH: parathyroid hormone RSS: Rickets Severity Score SD: standard deviation TOF: 3D time-of-flight XLH: X-linked hypophosphatemic rickets Declarations Ethics approval and consent to participate This study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Campania 2 Ethics Committee, prior to the initiation of the study. All participants (or their legal guardians) provided written informed consent before inclusion. The ethics committee reviewed and approved all study procedures, including data collection and handling. Documentation confirming ethical approval is available upon request by the Editor. Consent for Publication Written informed consent for publication of the data and any accompanying images was obtained from a parent or legal guardian of the partecipants) involved in this study. Documentation confirming consent is available for review by the Editor upon request. Data Availability Statement The datasets generated for this study have been included in the main manuscript and supplemental material. Further information will be provided by the corresponding author upon reasonable request. Competing Interest The authors declare that they have no competing interests Funding This research received specific found fromthe Agreement for the Cohesion of the Campania Region. Revolving Fund pursuant to Law 183/1987 with the project RachiExtra Author Contributions AG conceptualized the paper and reviewed the manuscript. BG reviewed all the data and the drafting of the manuscript. FA wrote the original draft and managed the data curation, performed the literature review. FR managed the data curation and helped in writing process. FeAl performed the neuroradiological evaluation. EMDG handle clinical data curation and supervised the paper. MC and RC performed the neuroradiological investigation and contributed to images selections. GC supervised the whole work and administrate the project. All authors read and approved the final manuscript. Acknowledgments We acknowledge patient family for sharing their clinical data for research and science improvement References Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol. 2009;160:491–497. Endo I, Matsumoto T, Ogata N, et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocr J. 2015;62:811–816. 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PLoS One. 2009;4:e7120. doi:10.1371/journal.pone.0007120. Park SS, Beyer RP, Smyth MD, Clarke CM, Timms AE, Bammler TK, et al. Osteoblast differentiation profiles define sex-specific gene expression patterns in craniosynostosis. Bone. 2015;76:169–176. doi:10.1016/j.bone.2015.03.001. Murali SK, Andrukhova O, Clinkenbeard EL, White KE, Erben RG. Excessive osteocytic FGF23 secretion contributes to pyrophosphate accumulation and mineralization defect in Hyp mice. PLoS Biol. 2016;14:e1002427. doi:10.1371/journal.pbio.1002427. Grimbly C, Graf D, Ward LM, Alexander RT. X-linked hypophosphatemia, fibroblast growth factor 23 signaling, and craniosynostosis. Exp Biol Med (Maywood). 2023;248:2175–2182. doi:10.1177/15353702231222023. Iorio RJ, Murray G, Meyer RA. Craniometric measurements of craniofacial malformations in mice with X-linked, dominant hypophosphatemia (vitamin D-resistant rickets). Teratology. 1980;22:291–298. doi:10.1002/tera.1420220305. Caldemeyer KS, Boaz JC, Wappner RS, Moran CC, Smith RR, Quets JP. Chiari I malformation: association with hypophosphatemic rickets and MR imaging appearance. Radiology. 1995;195:733–738. doi:10.1148/radiology.195.3.7754003. Miyagawa K, Yamazaki M, Kawai M, Nishino J, Koshimizu T, Ohata Y, Tachikawa K, Mikuni-Takagaki Y, Kogo M, Ozono K, Michigami T. Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice. PLoS One. 2014;9:e93840. Xiao Z, Huang J, Cao L, Liang Y, Han X, Quarles LD. Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS One. 2014;9:e104154. Miyagawa K, Yamazaki M, Kawai M, Nishino J, Koshimizu T, Ohata Y, Tachikawa K, Mikuni-Takagaki Y, Kogo M, Ozono K, Michigami T. Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice. PLoS One. 2014;9:e93840. Jaszczuk P, Rogers GF, Guzman R, Proctor MR. X-linked hypophosphatemic rickets and sagittal craniosynostosis: three patients requiring operative cranial expansion: case series and literature review. Childs Nerv Syst. 2016;32:887–891. doi:10.1007/s00381-015-2934-9. Freudlsperger C, Hoffmann J, Castrillon-Oberndorfer G, Engel M. Bilateral coronal and sagittal synostosis in X-linked hypophosphatemic rickets: a case report. J Craniomaxillofac Surg. 2013;41:842–844. doi:10.1016/j.jcms.2013.01.039. Glass LR, Dagi TF, Dagi LR. Papilledema in the setting of X-linked hypophosphatemic rickets with craniosynostosis. Case Rep Ophthalmol. 2011;2:376–381. doi:10.1159/000334941. Murthy AS. X-linked hypophosphatemic rickets and craniosynostosis. J Craniofac Surg. 2009;20:439–442. doi:10.1097/SCS.0b013e31819b9868. Willis FR, Beattie TJ. Craniosynostosis in X-linked hypophosphataemic rickets. J Paediatr Child Health. 1997;33:78–79. doi:10.1111/j.1440-1754.1997.tb00997.x. Fourikou M, Karipiadou A, Ververi A, Savvidou P, Laliotis N, Tsitouras V, et al. X-linked hypophosphatemia due to a de novo novel splice-site variant in a 7-year-old girl with scaphocephaly, Chiari syndrome type I and syringomyelia. Bone Rep. 2023;20:101731. doi:10.1016/j.bonr.2023.101731. Lee KS, Lee BL. The first Korean case report with scaphocephaly as the initial sign of X-linked hypophosphatemic rickets. Childs Nerv Syst. 2019;35:1045–1049. doi:10.1007/s00381-018-04042-7. Vakharia JD, Matlock K, Taylor HO, Backeljauw PF, Topor LS. Craniosynostosis as the presenting feature of X-linked hypophosphatemic rickets. Pediatrics. 2018;141:S515–S519. doi:10.1542/peds.2017-2522. Migliarino V, Magnolato A, Barbi E. Twin girls with hypophosphataemic rickets and papilloedema. Arch Dis Child Educ Pract Ed. 2022;107:124–126. doi:10.1136/archdischild-2020-319615. Mellanen A, Kuusela L, Leikola J, Karppinen A, Autti T, Virtanen P, Brandstack N. Comparison of Black Bone MRI and 3D-CT in the preoperative evaluation of patients with craniosynostosis. J Plast Reconstr Aesthet Surg. 2020;73:723–731. doi:10.1016/j.bjps.2019.11.006. Montoya JC, Eckel LJ, DeLone DR, Kotsenas AL, Diehn FE, Yu L, et al. Low-dose CT for craniosynostosis: preserving diagnostic benefit with substantial radiation dose reduction. AJNR Am J Neuroradiol. 2017;38:672–677. doi:10.3174/ajnr.A5063. Eley KA, Watt-Smith SR, Sheerin F, Golding SJ. “Black Bone” MRI: a potential alternative to CT with three-dimensional reconstruction of the craniofacial skeleton in the diagnosis of craniosynostosis. Eur Radiol. 2014;24:2417–2426. doi:10.1007/s00330-014-3286-7. Tables Tables 1 and 2 are available in the Supplementary Files section Supplementary Files Tables.docx supplementarycraniostenosiinXLH04.11.25.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 21 Nov, 2025 Reviewers invited by journal 19 Nov, 2025 Editor invited by journal 19 Nov, 2025 Editor assigned by journal 18 Nov, 2025 First submitted to journal 16 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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1","display":"","copyAsset":false,"role":"figure","size":127858,"visible":true,"origin":"","legend":"\u003cp\u003eFlow\u003cstrong\u003e \u003c/strong\u003ediagram of neuroradiological evaluation\u003c/p\u003e","description":"","filename":"Figure1XLHandcraniosynostosis.png","url":"https://assets-eu.researchsquare.com/files/rs-8107500/v1/c94700610625026269e3a901.png"},{"id":97096108,"identity":"1a9947db-471f-480f-9276-48ed884d504d","added_by":"auto","created_at":"2025-11-30 23:28:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":600359,"visible":true,"origin":"","legend":"\u003cp\u003e3D CT Skull Reconstruction in a Patient with XLH- associated craniosynostosis\u003c/p\u003e","description":"","filename":"figure2XLHandcraniosynostosis.png","url":"https://assets-eu.researchsquare.com/files/rs-8107500/v1/f660cfe8f7d897cca240dc58.png"},{"id":97096109,"identity":"6d90b196-21b9-4f85-ae4c-9143a4232777","added_by":"auto","created_at":"2025-11-30 23:28:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":804713,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBrain MRI Showing Arnold-Chiari Type I Malformation in a Patient with XLH\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA)\u003c/strong\u003eSagittal brain MR image: Hindbrain herniation is evident with cerebellar tonsil protrusion through the foramen magnum, identified by the basion-opistion line (\u003cstrong\u003ered line)\u003c/strong\u003e. Note the dolicocephalic shape of the cranial vault. \u003cstrong\u003eB)\u003c/strong\u003e Axial brain MR image: Optic nerve sheath ectasia (\u003cstrong\u003ered arrow\u003c/strong\u003e). \u003cstrong\u003eC)\u003c/strong\u003e 3D-TOF sequences in coronal view: Absence of a flow signal in the transverse venous sinuses (\u003cstrong\u003ewhite arrows\u003c/strong\u003e) \u003cstrong\u003eD)\u003c/strong\u003e3D-TOF sequences in sagittal view: collateral circulation (\u003cstrong\u003eyellow arrow\u003c/strong\u003e)\u003c/p\u003e","description":"","filename":"figure3XLHandcraniosynostosis.png","url":"https://assets-eu.researchsquare.com/files/rs-8107500/v1/23935c637739b9c70b3c583b.png"},{"id":97096103,"identity":"87128bd4-92a5-4806-915f-f370b46a351d","added_by":"auto","created_at":"2025-11-30 23:28:07","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":177517,"visible":true,"origin":"","legend":"\u003cp\u003eBlack Bone MRI sequence in the axial plane at the level of the bregma in Patient 11.\u003c/p\u003e\n\u003cp\u003eThe image highlights the coronal sutures (indicated by the red arrow) and the sagittal suture (indicated by the yellow arrow).\u003c/p\u003e","description":"","filename":"figure4XLHandcraniosynostosis.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8107500/v1/4b6d157d1933138532cb4531.jpg"},{"id":97145145,"identity":"79340741-f296-4f64-86b5-6f344df954be","added_by":"auto","created_at":"2025-12-01 10:13:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2458100,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8107500/v1/c8dd6607-caad-4468-9400-3a6513f0463d.pdf"},{"id":97140556,"identity":"fd26b48f-d600-463c-8e90-9137b85a33d5","added_by":"auto","created_at":"2025-12-01 10:05:15","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23087,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-8107500/v1/51588eae9eb2f9c92ce733ed.docx"},{"id":97096102,"identity":"a97e4851-83a3-46d7-9539-adf49f9636fd","added_by":"auto","created_at":"2025-11-30 23:28:07","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":32462,"visible":true,"origin":"","legend":"","description":"","filename":"supplementarycraniostenosiinXLH04.11.25.docx","url":"https://assets-eu.researchsquare.com/files/rs-8107500/v1/3a5befc7b4d517b57aa906c9.docx"}],"financialInterests":"","formattedTitle":"Craniosynostosis in Children with X-Linked Hypophosphatemia Treated with Burosumab: Insights from a Single Center Cross-sectional Cohort Screening","fulltext":[{"header":"Highlights","content":"\u003cul\u003e\n \u003cli\u003e\u003cem\u003eCS was common in a cohort of XLH children(41.7%), mostly involving sagittal fusion.\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eDolicocephaly and male sex were associated with CS.\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eChiari malformation type 1 was common in CS patients.\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eAge and dose at burosumab start did not differ between CS and non-CS patients.\u003c/em\u003e\u003c/li\u003e\n \u003cli\u003e\u003cem\u003eBlack bone MRI is a valuable radiation-free imaging option for studying suture patency.\u003c/em\u003e\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"1.\tBackground","content":"\u003cp\u003eX-linked hypophosphatemic rickets (XLH) \u0026nbsp;is a rare hereditary disorder caused by mutations in the \u003cem\u003ePHEX\u003c/em\u003e gene. It is characterized by elevated levels of fibroblast growth factor 23 (FGF23), wasting of renal phosphate, and active rickets. The incidence of XLH is estimated at 3.9 per 100,000 live births, with a prevalence ranging from 1.7 to 4.8 per 100,000 individuals [1,2]. Currently, XLH is the most common form of rickets in developed countries. The first clinical signs typically appear within the first two years of life, with affected children exhibiting lower extremity deformities and a waddling gait upon reaching walking age, accompanied by bone pain and progressively disproportionate short stature [3, 4, 5]. Over time, dental hypomineralization increases the risk of tooth abscesses and periodontitis [6]. In adulthood, patients frequently experience hearing loss, pseudofractures due to osteomalacia, osteoarthritis, enthesopathies, and spinal stenosis, all of which contribute to reduced quality of life [7].\u003c/p\u003e\n\u003cp\u003eComplete or partial ossification of cranial sutures, known as craniosynostosis (CS), is a potential complication of XLH. This altered ossification process causes cranial dysmorphia, reduced intracranial volume, and secondary abnormally high intracranial pressure [8,9]. CS remains an underrecognized manifestation of XLH, with limited research on its prevalence, age of onset, main factors influencing suture fusion, and related symptoms. A recent systematic review estimated a pooled prevalence of 22%, with significant variation among studies due to differences in diagnostic criteria, methodologies, and patient descriptions [10].\u003c/p\u003e\n\u003cp\u003eRecent evidence-based guidelines from 2025 recommend performing a fundoscopic examination and/or brain imaging only in patients presenting with headache, neck pain, or papilledema [11]. Additionally, most published data on neurosurgical complications preceded the introduction of novel treatment options for XLH.\u003c/p\u003e\n\u003cp\u003eBefore 2018, the standard treatment for XLH involved oral phosphate supplementation combined with active vitamin D metabolites. In 2018, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved burosumab, a fully human recombinant IgG1 monoclonal antibody targeting FGF23, for the treatment of XLH in children over one year of age and in adults [12]. To date, no studies have evaluated the impact of burosumab therapy on neurosurgical complications.\u003c/p\u003e\n\u003cp\u003eThis observational cross-sectional study aimed to investigate the prevalence of CS and its associated symptoms and complications in a cohort of twelve children with XLH receiving burosumab treatment. Black bone magnetic resonance imaging (MRI) in a subgroup, a radiation-free imaging technique, was used as a secondary method to assess suture patency.\u003c/p\u003e"},{"header":"2.\tMethods","content":"\u003cp\u003eThis observational, cross-sectional, single-center study was conducted on a pediatric population of twelve children with XLH who were followed at the Endocrinology Service of the Department of Woman, Child, General, and Specialized Surgery at the University of Campania “Luigi Vanvitelli,” Naples. All neurosurgical evaluations were performed by the Craniofacial Unit of the Neurosurgical Department at Santobono Children's Hospital, Naples, Italy, which is an integral part of our multidisciplinary team for neurosurgical assessment and patient management.\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Ethics Committee of the University of Campania “Luigi Vanvitelli.” In accordance with the World Medical Association Declaration of Helsinki, written informed consent was obtained from parents, and oral assent was collected from all participants.\u003c/p\u003e\n\u003cp\u003ePatients were enrolled for neuroradiological evaluation between January 1, 2023, and May 31, 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.1 Population and clinical parameters\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwelve pediatric patients (four males) with a molecular diagnosis of XLH were recruited for this study. The mean age at diagnosis was 2.5 ± 1.0 years (range: 10 months to 3.5 years). Each patient underwent a comprehensive clinical and neuroradiological assessment. The mean age at neuroradiological examination was 8.3 ± 4.6 years.\u003c/p\u003e\n\u003cp\u003eThe following anthropometric parameters were recorded at the time of evaluation: height, growth velocity, weight, pubertal stage, and head circumference. Measurements were performed via standardized equipment: a Wunder Sa. BI scale for weight and a HILTI PD30 digital altimeter for height. To minimize measurement bias, each parameter was assessed three times. Cacciari growth curves stratified by sex and age were used for the standardization of the anthropometric assessments [13].\u003c/p\u003e\n\u003cp\u003eAt the time of neuroradiological evaluation, the following biochemical parameters were collected for each patient: serum calcium, phosphate, creatinine, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D (1,25(OH)\u003csub\u003e2\u003c/sub\u003eD), alkaline phosphatase (ALP), bone isoenzyme of alkaline phosphatase (BALP), and urinary excretion of calcium, phosphate, and creatinine. All laboratory analyses were conducted at the central laboratory of A.O.U. “L. Vanvitelli”. Serum 25OHD, 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD, and PTH levels were measured via the CLIA DiaSorin® immunoassay method, whereas serum electrolytes, creatinine, and ALP and BALP were analyzed via the Architect immunoassay (Abbott kit®). The TmP/GFR was assessed via the method of Stark et al. [14].\u003c/p\u003e\n\u003cp\u003eThe Rickets Severity Score (RSS) was determined at the time of neuroradiological evaluation on the basis of wrist and knee X-ray scans. Scoring was performed by a single orthopedic specialist with expertise in metabolic bone disorders. The total RSS was calculated as the sum of the wrist score (ranging from 0 to 4) and the knee score (ranging from 0 to 6), with higher scores indicating more severe manifestations of rickets [15].\u003c/p\u003e\n\u003cp\u003eMedical records were reviewed to retrieve anthropometric and clinical data prior to the initiation of burosumab therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2 Neuroradiological evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 illustrates the neuroradiological assessment procedures of the patients in our cohort. Briefly, neuroradiological evaluation was offered to all patients who were able to undergo a complete brain computed tomography (CT) scan, even in the absence of neurological symptoms. MRI was performed in all patients with craniosynostosis and in three patients without craniosynostosis. All skull CT scans were performed at the Neuroradiology Unit of A.O.U. “Luigi Vanvitelli,” whereas MRIs were conducted either at the same institution or at the Neuroradiology Unit of Santobono Pausilipon Children’s Hospital in cases requiring sedation (four patients).\u003c/p\u003e\n\u003cp\u003eIndividuals diagnosed with\u0026nbsp;CS were subjected to an extensive neurological assessment encompassing funduscopic examination, cranial nerve evaluation, tests of coordination and balance, and recording of somatosensory and motor evoked potentials.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.1 TC scans\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThree-dimensional rendering of skull CT scans was performed to evaluate suture patency. Sagittal section multiplanar reconstruction (MPR) allows the calculation of the cranial index (CI) and skull base angle (sellar-basion-nasion angle). The CI was expressed as the percentage ratio of transverse-to-anteroposterior diameters. A CI \u0026lt;75% was diagnostic for dolichocephaly, whereas a CI between 75% and 80% indicated mesocephaly [16].\u003c/p\u003e\n\u003cp\u003ePlatybasia, characterized by abnormal flattening of the skull base, was assessed via the Welcher basal angle, which is formed at the intersection of lines drawn from the nasion to the tuberculum sella and from the basion to the tuberculum. The average Welcher basal angle is 132° and is considered normal when \u0026lt;140°. Platybasia is defined by a Welcher basal angle \u0026gt;140° [17].\u003c/p\u003e\n\u003cp\u003eThe position of the cerebellar tonsils in sagittal sections was evaluated for the diagnosis of Chiari type I malformation (CM-I), which is defined as the descent of the cerebellar tonsils \u0026gt;5 mm through the foramen magnum as identified by the basion-opistion line[18].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.2 Brain MRI\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients with\u0026nbsp;CS underwent brain MRI to assess brain morphology via T1, T2, and FLAIR sequences. Additionally, angio-MRI with 3D time-of-flight (TOF) sequencing was performed in two patients. Four patients underwent MRI under general anesthesia.\u003c/p\u003e\n\u003cp\u003eTo evaluate whether brain MRI resolution could effectively detect suture patency, three patients without\u0026nbsp;CS who did not require sedation underwent MRI with black bone sequencing at the Neuroimaging Research Center of A.O.U. “Luigi Vanvitelli”.\u003c/p\u003e\n\u003cp\u003eA 3-Tesla MRI with black bone sequences provided a low flip angle, gradient echo (GRE) MRI sequence, yielding high image contrast between the bone and surrounding tissues. Images were acquired in the axial plane via a three-dimensional GRE sequence. The flip angle was incrementally reduced from 60° to 5° while maintaining a short echo time (4.2 ms) and repetition time (8.6 ms). The remaining scanning parameters are detailed in supplemental Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. 1\u0026nbsp;\u003c/strong\u003eFlowdiagram of neuroradiological evaluation\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; [ Insert figure 1]\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3 Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data were analyzed via SPSS 28.0 software (International Business Machines Corporation). Descriptive statistics were applied to characterize the whole cohort, and the data are presented as frequencies or means and standard deviations (SDs) as appropriate. Lilliefors’ test was run to investigate the normal distribution: nonparametric data were analyzed via the Mann‒Whitney U test, whereas a two-tailed Student’s t test was performed for parametric analysis. For correlation analysis, a Pearson correlation coefficient was calculated. Statistical significance was set at p \u0026lt; 0.05.\u003c/p\u003e"},{"header":"3.\tResults","content":"\u003cp\u003e\u003cstrong\u003e3.1\u0026nbsp;Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 summarizes the clinical and biochemical findings of the entire cohort before burosumab treatment and at the time of neuroradiological evaluation.\u003c/p\u003e\n\u003cp\u003eEach patient received conventional therapy with oral phosphate supplements and active vitamin D metabolites since diagnosis for a mean period of 36.2±35 months (median 24.9 months, range: 4.0–88.1) before starting burosumab. All patients demonstrated good treatment adherence, except for three patients (Pt 2, 8 and 12). The final mean elemental phosphorus dose before discontinuation was 41.3±23 mg/kg body weight (range: 20–80) divided into 4 daily doses associated with alfacalcidiol (mean dose 33±2.2 ng/kg/daily) or calcitriol (3 patients, mean dose 21 ng/kg/daily). None of the patients exhibited nephrocalcinosis or secondary/tertiary hyperparathyroidism while receiving oral phosphate supplements or active vitamin D metabolite therapy.\u003c/p\u003e\n\u003cp\u003eAt the time of neuroradiological assessment, all patients were receiving burosumab for a mean duration of\u0026nbsp;27.6 ± 14.6 years (range 9–44). The starting dose of burosumab was 0.48±0.04 mg/kg/14 days and was tailored to 1.53±0.45 (range 0.8–2) at the time of neuroradiological evaluation.\u003c/p\u003e\n\u003cp\u003eAll patients demonstrated significant increases in their serum phosphate (p=0.02) and 1,25(OH)\u003csub\u003e2\u003c/sub\u003eD levels (p=0.04) and TmP/GFR values (p=0.04). ALP and BALP levels were significantly lower in all patients (p\u0026lt;0.001). The RSS improved during burosumab treatment (p=0.02) (Table 1).\u003c/p\u003e\n\u003cp\u003eCirculating PTH levels, as well as serum calcium and calcium excretion, did not significantly change throughout treatment (data not shown). No adverse events related to burosumab treatment were observed in any patient. None of the patients developed hypercalcemia, hyperphosphatemia, nephrocalcinosis, or cardiac abnormalities throughout the treatment period.\u003c/p\u003e\n\u003cp\u003eThe results of general neurological examinations were within normal limits for all patients. No patient exhibited frank macrocephaly; however, 10 out of 12 patients demonstrated relative macrocephaly, defined as a head circumference measurement exceeding 2 SDSs above the individual's body size or other physical parameters. Headache was reported in four patients (Table\u0026nbsp;1).\u003c/p\u003e\n\u003cp\u003e[insert table 1]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2 Neuroradiological characterization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCT scan analysis revealed that 41.7% of patients (four males and one female) presented with CS together with a remarkably altered CI below 75%. Patient 1 exhibited complete fusion of the sagittal suture and partial closure of the coronal suture (see Figure 2 ). Patients 2, 3, and 4 presented with isolated complete sagittal suture fusion. Patient 5 had partial sagittal suture fusion. None of the patients presented with pansynostosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFig. 2\u0026nbsp;\u003c/strong\u003e 3D CT Skull Reconstruction in a Patient with XLH- associated craniosynostosis\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; [ Insert figure 2]\u003c/p\u003e\n\u003cp\u003eThe arrow in panel A indicates complete fusion of the sagittal suture, while the arrow in panel B highlights partial closure of the coronal suture\u003c/p\u003e\n\u003cp\u003eNo patient had a normal CI (\u0026gt;80%); altered skull morphology was observed in all patients, with seven patients without CS presenting mesocephaly and five patients with CS presenting dolichocephaly.\u003c/p\u003e\n\u003cp\u003eAn altered basal skull angle indicating platybasia was identified in one patient, with concurrent CM-I.\u003c/p\u003e\n\u003cp\u003eFor further details, refer to \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e[insert table 2]\u003c/p\u003e\n\u003cp\u003eMRI revealed CM-I in three patients with CS (Patients 1, 2, and 4), corresponding to a prevalence of 25% in the whole cohort and 60% in patients with CS. A statistically significant association was observed between CM-I and CS (p = 0.009, χ² test).\u003c/p\u003e\n\u003cp\u003eAngio-MRI in Patient 4 revealed optic nerve sheath ectasia and the absence of blood flow in both transverse sinuses, accompanied by parieto-occipital collateral compensatory circulation (see Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3. Brain MRI Showing Arnold-Chiari Type I Malformation in a Patient with XLH\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e[insert figure 3]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA)\u003c/strong\u003e Sagittal brain \u0026nbsp;MR image: Hindbrain herniation is evident with cerebellar tonsil protrusion through the foramen magnum, identified by the basion-opistion line (\u003cstrong\u003ered line)\u003c/strong\u003e. Note the dolicocephalic shape of the cranial vault. \u003cstrong\u003eB)\u003c/strong\u003e Axial \u0026nbsp;brain \u0026nbsp; MR image: Optic nerve sheath ectasia (\u003cstrong\u003ered arrow\u003c/strong\u003e). \u003cstrong\u003eC)\u003c/strong\u003e 3D-TOF sequences in coronal view: Absence of a flow signal in the transverse venous sinuses (\u003cstrong\u003ewhite arrows\u003c/strong\u003e) \u003cstrong\u003eD)\u003c/strong\u003e 3D-TOF sequences in sagittal view: \u0026nbsp; collateral circulation (\u003cstrong\u003eyellow arrow\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003eThe black bone RMI sequence, which was performed in three patients without CS to confirm the efficacy of this technique for visualizing cranial sutures, clearly showed suture patency, confirming the TC results. (see Figure 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFigure 4.\u003c/em\u003e\u003c/strong\u003e Black Bone MRI sequence in the axial plane at the level of the bregma in Patient 11.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e[Insert figure 4]\u003c/p\u003e\n\u003cp\u003eThe image highlights the coronal sutures (indicated by the red arrow) and the sagittal suture (indicated by the yellow arrow).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3 Characteristics of patients with CS vs patients without CS\u003cbr\u003e\u003c/strong\u003eCS was significantly associated with male sex (p = 0.0135, χ² test).\u003cbr\u003eCompared with patients without craniosynostosis (NO-CS), patients with CS presented a significantly greater head circumference SDS at the start of burosumab therapy (p = 0.015). This trend of increased head circumference persisted later in life during neuroradiological evaluation but did not reach statistical significance.\u003c/p\u003e\n\u003cp\u003eCI was significantly lower in patients with CS (CI = 70.1 ± 2.5%) than in those without CS (CI = 78.4 ± 1.8%, p \u0026lt;0.001). However, all patients exhibited skull shape alterations, including those without CS.\u003c/p\u003e\n\u003cp\u003eThe prevalence of headache was significantly greater in the CS group (p = 0.02); however, two patients with CS remained asymptomatic for headache, one of whom had associated CM1. No significant difference was found in the number of dental abscesses or the presence of hearing impairment between the two groups.\u003c/p\u003e\n\u003cp\u003eNo significant differences were observed in the age at initiation of burosumab therapy (p = 0.78). The duration of treatment was comparable between the groups, with a mean treatment period of 25.2 ± 17.5 months (range 0.6–11.0) in the CS group and 29.3 ± 10.4 months (range 0.3–7.3) in the NO-CS group (p = 0.45). No differences were found in the mean burosumab dosage (p = 0.68).\u003c/p\u003e\n\u003cp\u003eSubgroup analysis comparing patients with and without CS did not reveal any significant biochemical differences in calcium‒phosphate biochemical parameters before or after burosumab treatment (data not shown), except for a greater RSS at neuroradiological evaluation (p = 0.030) in patients with CS. CM-I was significantly associated with CS (p = 0.025). All the parameters analyzed for the subgroups are reported in Supplementary Table 2.\u003c/p\u003e\n\u003cp\u003eFunduscopic examination ruled out papilloedema in all patients with CS. Cranial nerve assessments confirmed normal visual acuity, pupillary reactions, facial symmetry, and hearing in all patients. The coordination and balance were preserved. Motor and sensory evaluations, including evoked motor and sensory potentials, ruled out focal neurological deficits in all patients. At present, no patient has met the criteria for surgical decompression or cranial hypertension intervention.\u003c/p\u003e"},{"header":"4.\tDiscussion","content":"\u003cp\u003eThis observational, cross-sectional study is the first to systematically examine patients with XLH while receiving burosumab therapy for CS, even in the absence of neurological symptoms. As expected, in our cohort, burosumab therapy improved phosphate metabolism and\u0026nbsp;rickets severity, indicating both effectiveness and safety in a real-world clinical setting.\u003c/p\u003e\n\u003cp\u003eFurthermore, our analysis revealed a 41.7% incidence of CS, all involving sagittal suture fusion, with one case also showing partial coronal suture closure. This rate exceeds the 22% pooled prevalence reported by Fisch et al. [10], indicating heterogeneity among studies. Previous studies by Rothenbuhler et al. [20] and Arenas et al. [21] reported elevated rates of CS (67% and 52%, respectively). In particular, our data align with those of Arenas et al., who analyzed a cohort of both symptomatic and asymptomatic patients, similar to our study.\u003c/p\u003e\n\u003cp\u003eCompared with the general pediatric population, in which CS may occur in ~1 per 2,100–2,500 births [22], XLH patients have a markedly increased risk of CS. The variability in reported prevalence may be due to differences in study design. Unlike retrospective reports, our study prospectively screened genetically confirmed XLH patients, avoiding diagnostic bias.\u003c/p\u003e\n\u003cp\u003eWith respect to the type of CS, sagittal suture involvement was present in all affected individuals in our cohort. Fisch et al. [10] reported that sagittal synostosis was present in 42% to 100% of patients with XLH and CS, unlike patients with idiopathic CS, where sagittal fusion appeared in 40%-78% of patients [23].\u003c/p\u003e\n\u003cp\u003eThe median age at evaluation of our patients was 8.3 years; however, no definitive information can be provided regarding the average age of CS onset. A recent literature review by Munns et al. [24] reported a median age of diagnosis of approximately 2 years, in which patients were referred for neurosurgical evaluation due to symptoms or clinical signs of CS [8, 24, 25].\u003c/p\u003e\n\u003cp\u003eOur study revealed that the evolution of the CS in XLH patients can be silent and insidious, as 2 of our 5 CS patients did not present with headache or neurological signs.\u003c/p\u003e\n\u003cp\u003eInterestingly, morphological skull assessment revealed shape alterations in all our patients: dolichocephaly in all CS patients and mesocephaly in all the other patients. Moreover, relative macrocephaly, defined by head circumference \u0026gt;2 SDs above the height percentile, was identified in all CS patients. Before burosumab treatment, individuals affected by CS had significantly greater head circumferences, although the differences were not statistically significant at the neuroradiological evaluation. However, we cannot determine whether this difference could be attributable to the effect of burosumab on skull shape.\u003c/p\u003e\n\u003cp\u003eThese findings emphasize the value of head circumference monitoring and careful head shape observation in XLH patients to perform early imaging; however, skull morphology is not sufficient to identify patients with CS.\u003c/p\u003e\n\u003cp\u003eA statistically significant correlation of CS with male sex was found despite XLH being more common in females. In the meta-analysis by Fisch et al. [10], sex prevalence was available in 4 out of 10 studies analyzed, with reported male prevalence rates ranging from 46% [8] to 100% [26]. Experimental models support this sex bias: male Hyp mice display more severe craniofacial abnormalities [27]. The protective effect of the unaffected \u003cem\u003ePHEX\u003c/em\u003e allele in heterozygous females may partially explain this trend [28]. Male predominance has also been noted in nonsyndromic CS [29, 30], likely due to sex-related hormonal and transcriptional effects on osteogenesis [31,32]. These findings suggest that male sex itself may be associated with greater phosphate metabolism imbalance, contributing to CS susceptibility.\u003c/p\u003e\n\u003cp\u003eCS was associated with a higher RSS and a trend toward higher ALP levels during burosumab treatment, suggesting a possible link to more severe disease or less responsiveness to treatment. No associations were found between burosumab initiation age, treatment duration, and CS occurrence. Owing to the small sample size and the lack of neuroradiological investigations before starting burosumab, no conclusions regarding the impact of burosumab on suture closure can be drawn. However, two of the five patients diagnosed with CS started burosumab therapy within the first two years of life. This may suggest that the cellular mechanisms underlying CS due to phosphate metabolism dysregulation are established at an even earlier developmental stage.\u003c/p\u003e\n\u003cp\u003ePreclinical data from Hyp mice indicate that suture abnormalities appear by three weeks of age [33], with heightened expression of FGFR1/FGFR2 observed even before birth [34]. These findings support FGF/FGFR signaling as a driver of CS, potentially through the upregulation of FGF23 [34, 35]. Such mechanisms may explain early and frequent suture pathology in XLH and require further investigation.\u003c/p\u003e\n\u003cp\u003eCM-I was present in 60% of XLH patients with CS, reinforcing a link between suture fusion and posterior fossa dynamics, as reported by Caldemeyer et al. [36] and Rothenbuhler et al. [20]. The strong association between CM-I and sagittal synostosis suggested that cerebellar descent may result from decreased cranial compliance during brain growth, a phenomenon underrecognized in isolated scaphocephaly. This distinction implies different natural histories in XLH, challenging the extrapolation of natural history, prognosis, and surgical indications from isolated conditions to XLH. Not all patients with CM-I presented headache; therefore, this symptom cannot be reliable for deciding which patient to screen. Nevertheless, in children with XLH receiving conventional treatment or burosumab, in the presence of CS or skull shape malformation, headache, neurological symptoms or visual disturbances, or suspected spinal stenosis on the basis of clinical symptoms, brain/spine MRI has been suggested [37].\u003c/p\u003e\n\u003cp\u003eNone of our patients required surgical intervention. The specific indications for surgical intervention in XLH patients remain unclear.\u003c/p\u003e\n\u003cp\u003eTwenty-one cases of children with XLH and CS who underwent neurosurgery have been reported thus far\u0026nbsp;[9, 20, 36-49] (Supplemental Table 3). The median age at neurosurgical referral in these reports was 3 years, and the mean age at surgery was 4 years. Sagittal suture fusion was the most frequent abnormality (16 patients). Combined suture fusion occurred in three patients; the suture type was unspecified in two patients.\u003c/p\u003e\n\u003cp\u003eMost patients exhibited signs of cranial hypertension; eight had subclinical intracranial pressure elevation. Strabismus emerged as a key sign of increased ICP in three patients. CM-I was reported in four children. Owing to the older age at diagnosis and treatment, the most common surgical technique was cranial vault remodeling (9 patients), followed by craniectomy (5 patients) and parietal plastic surgery (2 patients). Four papers did not report the procedure.\u003c/p\u003e\n\u003cp\u003eThe outcomes were favorable, with no reinterventions during a median follow-up of 21 months (range: 6–60 months). However, outcome data were lacking for over half of the patients.\u003c/p\u003e\n\u003cp\u003eDespite the high prevalence of CS, the need for surgery in XLH patients is lower than that in patients with isolated CS, likely due to delayed diagnosis and milder clinical presentation. Late surgery may impair optimal aesthetic outcomes. Therefore, surgery is probably reserved for patients with intracranial hypertension in the XLH setting.\u003c/p\u003e\n\u003cp\u003eFinally, black bone MRI, performed in three of our patients, demonstrated high reliability in assessing cranial suture patency. While CT remains the diagnostic gold standard for assessing CS due to its high-resolution bone imaging ability and 3D rendering capability, it involves ionizing radiation exposure. To mitigate this, low-dose CT has gained traction, as shown by Montoya et al. [51]; however, its limited soft-tissue resolution hinders the detection of intracranial anomalies.\u003c/p\u003e\n\u003cp\u003eIn recent years, MRI of the cranial vault has become increasingly valuable, particularly in pediatric populations [52] requiring repeated imaging. MRI avoids ionizing radiation and offers superior visualization of complications such as hydrocephalus and tonsillar herniation. Black bone MR sequences provide detailed imaging of both cranial sutures and associated anomalies, including CM-I [53].\u003c/p\u003e\n\u003cp\u003eOur study has several limitations, including the small cohort and the lack of data on the age at onset of CS or cerebellar descent. Furthermore, owing to the study design, no definite data regarding the potential efficacy of burosumab for treating CS can be inferred. Nonetheless, our results reported the prevalence of CS in a cohort of asymptomatic or paucisymptomatic children with XLH, some of whom started burosumab at quite an early age. These findings indicate the utility of neuroradiological screening in XLH patients, particularly in males, where a low CI may be the only indicator of CS, even in the presence of associated CM-I.\u003c/p\u003e\n\u003cp\u003eBrain MR images, specifically black bone sequences, represent a promising, nonionizing alternative to CT scans for screening CM-I associated with CS.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study provides the first comprehensive neuroradiological screening of CS in children with XLH undergoing burosumab therapy, reinforcing the hypothesis that CS is a significant and underrecognized feature of XLH. While no clear impact of burosumab on suture closure was identified due to sample size and study limitations, the findings emphasize the need for regular monitoring.\u003c/p\u003e\n\u003cp\u003eImportantly, black bone MRI has emerged as a viable, radiation-free alternative to CT for evaluating suture patency and detecting associated anomalies.\u003c/p\u003e\n\u003cp\u003eOur findings call for proactive surveillance strategies at XLH, and routine neuroimaging and cranial morphometry may support early detection. Future studies should expand investigations into adult XLH patients and evaluate the long-term consequences of skull and cranio-vertebral anomalies.\u003c/p\u003e\n\u003cp\u003eLongitudinal studies are warranted to clarify the natural history of craniosynostosis in XLH and to assess the potential effects of burosumab.\u003c/p\u003e"},{"header":"Abbreviation","content":"\u003cp\u003e1,25(OH)\u003csub\u003e2\u003c/sub\u003eD : 1,25-dihydroxyvitamin D\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e25OHD: 25-hydroxyvitamin D\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eALP: alkaline phosphatase\u003c/p\u003e\n\u003cp\u003eBALP: bone isoenzyme of alkaline phosphatase\u003c/p\u003e\n\u003cp\u003eCI: cranial index \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCM-I: Chiari type I malformation\u003c/p\u003e\n\u003cp\u003eCS: craniosynostosis \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCT: computed tomography\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEMA: European Medicines Agency\u003c/p\u003e\n\u003cp\u003eFDA Food and Drug Administration \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFGF23: fibroblast growth factor 23\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGRE: gradient echo \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRI: magnetic resonance imaging \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePTH: parathyroid hormone\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRSS: Rickets Severity Score \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSD: \u0026nbsp;standard deviation\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTOF: \u0026nbsp;3D time-of-flight \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eXLH: X-linked hypophosphatemic rickets\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the principles of the Declaration of Helsinki. Ethical approval was obtained from the Campania 2 Ethics Committee, prior to the initiation of the study. All participants (or their legal guardians) provided written informed consent before inclusion. The ethics committee reviewed and approved all study procedures, including data collection and handling. Documentation confirming ethical approval is available upon request by the Editor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of the data and any accompanying images was obtained from a parent or legal guardian of the partecipants) involved in this study. Documentation confirming consent is available for review by the Editor upon request.\u003c/p\u003e\n\u003cp\u003eData Availability Statement\u003c/p\u003e\n\u003cp\u003eThe datasets generated for this study have been included in the main manuscript and supplemental material. Further information will be provided by the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research \u0026nbsp; \u0026nbsp;received \u0026nbsp; specific found fromthe Agreement for the Cohesion of the Campania Region. Revolving Fund pursuant to Law 183/1987 with the project RachiExtra\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAG conceptualized the paper and reviewed the manuscript. BG reviewed all the data and the drafting of the manuscript. FA wrote the original draft and managed the data curation, performed the literature review. FR managed the data curation and helped in writing process. FeAl performed the neuroradiological evaluation. EMDG handle clinical data curation and supervised the paper. MC and RC performed the neuroradiological investigation and contributed to images selections. GC \u0026nbsp;supervised the whole work and administrate the project. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge patient family for sharing their clinical data for research and science improvement\u003c/p\u003e"},{"header":"References ","content":"\u003col\u003e\n\u003cli\u003eBeck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol. 2009;160:491\u0026ndash;497.\u003c/li\u003e\n\u003cli\u003eEndo I, Matsumoto T, Ogata N, et al. Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. 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Pediatrics. 2018;141:S515\u0026ndash;S519. doi:10.1542/peds.2017-2522.\u003c/li\u003e\n\u003cli\u003eMigliarino V, Magnolato A, Barbi E. Twin girls with hypophosphataemic rickets and papilloedema. Arch Dis Child Educ Pract Ed. 2022;107:124\u0026ndash;126. doi:10.1136/archdischild-2020-319615.\u003c/li\u003e\n\u003cli\u003eMellanen A, Kuusela L, Leikola J, Karppinen A, Autti T, Virtanen P, Brandstack N. Comparison of Black Bone MRI and 3D-CT in the preoperative evaluation of patients with craniosynostosis. J Plast Reconstr Aesthet Surg. 2020;73:723\u0026ndash;731. doi:10.1016/j.bjps.2019.11.006.\u003c/li\u003e\n\u003cli\u003eMontoya JC, Eckel LJ, DeLone DR, Kotsenas AL, Diehn FE, Yu L, et al. Low-dose CT for craniosynostosis: preserving diagnostic benefit with substantial radiation dose reduction. AJNR Am J Neuroradiol. 2017;38:672\u0026ndash;677. doi:10.3174/ajnr.A5063.\u003c/li\u003e\n\u003cli\u003eEley KA, Watt-Smith SR, Sheerin F, Golding SJ. \u0026ldquo;Black Bone\u0026rdquo; MRI: a potential alternative to CT with three-dimensional reconstruction of the craniofacial skeleton in the diagnosis of craniosynostosis. Eur Radiol. 2014;24:2417\u0026ndash;2426. doi:10.1007/s00330-014-3286-7.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Arnold-Chiari Malformation, Black Bone MRI, Burosumab, Cephalic Index, Craniosynostosis, Dolicocephaly, Hypophosphatemic Rickets, Neuroradiography, X-Linked Dominant","lastPublishedDoi":"10.21203/rs.3.rs-8107500/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8107500/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX-linked hypophosphatemic rickets (XLH) is the most common genetic form of hypophosphatemia, caused by elevated FGF23 and renal phosphate wasting. Cranial anomalies such as craniosynostosis (CS) and Chiari type I malformation (CM-I) are reported in XLH, but prevalence data—especially in the context of burosumab therapy—remain limited. This monocentric study evaluated (a) the prevalence and predictors of CS and CM-I in children with XLH receiving burosumab, and (b) the utility of brain black bone MRI as a nonionizing alternative to computed tomography (CT).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwelve children (8.3 ± 4.6 years; four males) were assessed after a mean burosumab treatment duration of 28 ± 14.6 months. All were asymptomatic or paucisymptomatic for CS. Cranial morphology was evaluated via CT, and MRI was performed in patients with CS; three children without CS underwent MRI with black bone sequences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCS with sagittal suture fusion was present in 41.7% of patients, and CM-I in 25%. No patient had a normal cranial index(\u0026gt;80%).CS correlated significantly with male sex(p \u0026lt; 0.01), dolichocephaly(p \u0026lt; 0.001), and CM-I(p \u0026lt; 0.01). black bone sequences MRI successfully visualized sutures in children without CS. Burosumab improved phosphate metabolism and rickets, but showed no association with CS prevalence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSagittal suture fusion and CM-I are common in XLH, with male sex and dolichocephaly identified as strong predictors of CS. These findings underscore the importance of radiological screening in XLH and support MRI with black bone sequences as a promising diagnostic tool.\u003c/p\u003e","manuscriptTitle":"Craniosynostosis in Children with X-Linked Hypophosphatemia Treated with Burosumab: Insights from a Single Center Cross-sectional Cohort Screening","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-30 23:28:02","doi":"10.21203/rs.3.rs-8107500/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-11-21T16:42:05+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-19T16:59:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Orphanet Journal of Rare Diseases","date":"2025-11-19T10:30:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-18T11:20:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2025-11-16T13:21:31+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e1782608-1c2b-40df-b7e8-a8c10237f218","owner":[],"postedDate":"November 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-30T23:28:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-30 23:28:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8107500","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8107500","identity":"rs-8107500","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}