Clinical Features and Prognosis of Pediatric-Onset Erdheim-Chester Disease Compared with an Adult-Onset Cohort from the Same Center

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This study aimed to explored the distinctive characteristics of PECD. Methods This study compared the differences in clinical manifestations, laboratory/imaging characteristics, treatment responses, and outcomes between PECD and AECD from the same center and period. Results A total of 5 children with PECD and sixty-seven patients with AECD were ultimately included. Central nervous system and hypothalamic/pituitary involvement was frequently encountered in children (more than 50%). Pediatric-onset patients exhibited distinct patterns of organ involvement, with lower rates of bone involvement (60.0% vs. 97.0%; P = 0.022) and cardiac/large vessel involvement (0% vs. 65.7%; P = 0.007), compared with the AECD cohort. Analysis of osseous manifestations revealed significantly lower appendicular skeletal involvement in children [1/3 (33.3%) vs. 64/65 (98.5%); P = 0.004]. Osteosclerosis predominated in both children (2/3, 66.7%) and adults (52/62, 83.9%; P = 0.505), while approximately one-third exhibited osteolytic lesions in both groups. Comparative analysis revealed significantly lower levels of inflammatory markers ( P < 0.05) in the PECD group. Compared with the AECD cohort, patients with PECD showed a trend toward higher progression-free survival (80.0% vs. 35.0%, P = 0.196) and overall survival (100% vs. 80.5%, P = 0.382) rates. Conclusions PECD and AECD exhibit distinct differences in clinical manifestations and inflammatory response intensity. Pediatric patients appear to have better survival outcomes compared with adult patients. The consensus recommendations established for AECD may not be fully applicable to the pediatric population. Pediatric Erdheim-Chester disease clinical features prognosis Figures Figure 1 Figure 2 Figure 3 Figure 4 What is Known Erdheim-Chester disease (ECD) is a rare histiocytic disorder predominantly affecting middle-aged adults. Currently published consensus on diagnosis and management is more applicable to adult patients. Pediatric-onset ECD are infrequently reported, and their clinical features are incompletely characterized. What is New Pediatric-onset and adult-onset ECD differ in clinical manifestations and inflammation intensity. The consensus recommendations established for AECD may not be fully applicable to the pediatric population. Introduction Erdheim-Chester disease (ECD) is a rare histiocytic disorder first identified in 1930. It is distinguished by a diverse clinical spectrum that ranges from mild, localized symptoms to severe, multisystem disease. The diagnosis is typically established through histopathological examination of lesional tissues, which demonstrates the presence of CD68-positive and CD1a-negative foamy histiocytes, in conjunction with characteristic clinical manifestations and genetic alterations of BRAF mutations [ 1 ]. ECD predominantly affects middle-aged adults (AECD), with most diagnoses made between 46 and 56 years of age. Currently published consensus on diagnosis and management is more applicable to adult patients [ 2 ]. However, pediatric-onset ECD (PECD) may exhibit unique clinical manifestations. Pediatricians' limited familiarity with PECD may contribute to misdiagnosis. PECD is particularly uncommon, with the first well-documented case reported in 1991 [ 3 ]. This case demonstrated multisystem involvement (bone, pituitary, mediastinum, lung, kidney, etc.) and stabilized following surgical intervention and supportive care, suggesting that some patients with childhood-onset ECD may follow a benign course. The second pediatric case was not reported until 12 years later [ 4 ]. This patient also presented with multisystem involvement. Despite systemic chemotherapy using the Langerhans cell histiocytosis (LCH)-II protocol, intracranial lesions continued to progress. Subsequently, some cases were also refractory to corticosteroid combined with vinca alkaloid-based chemotherapy regimens [ 5 – 7 ]. Prior to the advent of targeted therapies, interferon α (IFNα) was the primary therapeutic approach [ 8 , 9 ]. Recent studies demonstrate that the mitogen-activated protein kinase (MAPK) pathway, particularly involving mutations in the BRAF gene, plays an important role in the pathogenesis of ECD. BRAF kinase inhibitors (such as vemurafenib and dabrafenib) show promising therapeutic value [ 2 ]. A literature review indicates that PECD cases are predominantly documented in isolated case reports. Although the largest single-center series to date included five children within a combined adult-pediatric cohort, this study did not conduct rigorous comparative analyses of phenotypic distinctions between pediatric and adult populations [ 10 ]. A recent multicenter study by Vaglio et al. [ 11 ] included patients with PECD (n = 13) and mixed ECD/LCH from 23 institutions. This study inadequately addresses the clinical differences between patients with PECD and AECD. However, key limitations—including ethnic heterogeneity, variable pathology/laboratory standards, and insufficient laboratory data—compromised the analysis. These limitations precluded an in-depth analysis of the distinctive clinical manifestations, laboratory/imaging characteristics, treatment responses, and outcomes between PECD and AECD. Managing PECD based on data and experiences derived from AECD cohorts may not represent the optimal approach. Our study addresses this gap through a comparative analysis of PECD and ethnically matched AECD from the same center. This approach aims to delineate disease-specific features and enhance pediatricians' understanding of PECD. Methods Patients and study design This retrospective study was conducted at Peking Union Medical College Hospital (PUMCH) and included patients aged less than 18 years who were diagnosed with PECD as the observation group between July 2012 and July 2022. The diagnosis of ECD in these patients was established based on characteristic histopathological findings (Fig. 1 a-d) independently confirmed by two pathologists according to the 2017 World Health Organization classification criteria (negative staining for CD1a, S100, or CD207 excludes mixed LCH/ECD). Additionally, patients were required to meet at least one of the following two criteria: (1) presence of at least one typical clinical manifestation of ECD; (2) positive detection of BRAF V600E mutation (Fig. 1 e). For comparative analysis, patients with AECD from the same period were included from our previously described cohort at the same center as the control group [ 12 ]. Clinical, laboratory, radiologic imaging and genetic data In this study, comprehensive clinical data were collected, including detailed demographic information (age, gender, etc.), thorough documentation of clinical presentations, and routine hematological tests such as white blood cell count, neutrophil count, and platelet count. Additionally, a panel of inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum ferritin (SF), fibrinogen, and cytokines (interleukin [IL]-6, IL-8, IL-10, and tumor necrosis factor-α) was evaluated. Radiological examinations, including radiography, high-resolution computed tomography, magnetic resonance imaging, bone scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT), were independently reviewed and interpreted by two radiologists. Genetic analysis for the BRAF V600E mutation was performed by polymerase chain reaction (PCR) on the pathological tissue in pediatric patients. In adults, the BRAF V600E mutation was detected by next-generation sequencing, PCR, or immunohistochemistry (IHC), as previously described [ 12 ]. Follow-up All patients were followed up through clinic visits or by telephone. The last follow-up time for PECD and AECD was December 31, 2024. Overall survival (OS) and progression-free survival (PFS) were used to assess patient outcomes. OS was defined as the duration from the date of ECD diagnosis to either the date of death or the last follow-up appointment, whichever occurred first. PFS was calculated from the date of diagnosis to the first occurrence of disease progression, relapse, or death from any cause, whichever came first. Treatment response was evaluated by modified PET Response Criteria in Solid Tumors using 18F-FDG PET-CT and cranial/pituitary magnetic resonance imaging with contrast [ 2 ]. Statistical analysis Statistical analyses were performed using IBM SPSS Statistics version 23.0. Non-normally distributed continuous variables were presented as median (IQR) and compared using the Mann-Whitney U test. Categorical data were expressed as numbers (percentages). Categorical variables were compared by chi-square test or Fisher's exact test as appropriate. Survival curves were estimated using the Kaplan-Meier method, and the log-rank test was used to compare the groups. Results General information A total of 5 children with PECD were included from our center (Table 1 ), comprising 4 male patients and 1 female patient, with a median age at diagnosis of 8.0 years (range: 4.4–12.1). The adult cohort comprised 71 patients with AECD. Four additional patients were excluded during follow-up due to concurrent other histiocytic disorders in three patients or acute myeloid leukemia in one patient. A total of 67 patients with AECD (control group) were ultimately included. Table 1 Clinical features of the single-center PECD cohort Involvement systems Treatment Follow-up period (months) Outcome Height Sequela Patient 1 (12.1y, M) bone, CNS, hypothalamic/pituitary, gallbladder, descending duodenum, lung and pleura prednisone + dabrafenib 40.6 CR P3-10 DI Patient 2 (10.4y, M) bone, CNS, hypothalamic/pituitary, lung vemurafenib→ dabrafenib 49.2 CR→relapse→PR P25-50 DI Patient 3 (5.1y, M) bone, skin, CNS, hypothalamic/pituitary prednisone + IFNα-2a 101.3 PR <P3 panhypopituitarism, osteochondral dysplasia Patient 4 (4.4y, M) CNS, lung, liver, kidney/retroperitoneal space IFNα-2a 91.0 PR (loss to follow-up after December 2022) lost to follow-up sensorineural hearing loss Patient 5 (8.0y, F) CNS observation after lesion resection surgery 43.8 SD P50-75 cognitive impairment, decreased attention Abbreviations: CNS central nervous system, CR complete response, DI diabetes insipidus, F female, IFN interferon, M male, PR partial response, SD stable disease Compared with the AECD cohort, the PECD cohort showed no statistically significant difference in gender distribution (males accounted for 80% vs. 46.3%, P = 0.193). The median time from symptom onset to definitive diagnosis was 8.9 months (IQR 5.2–36.2) in the PECD cohort, shorter than that in patients with AECD (27.1 months, IQR 10.1–56.5), though not statistically significant ( P = 0.308). Clinical manifestations Regarding initial presenting symptoms, among patients with PECD, three cases (60%) manifested polyuria/polydipsia as the primary symptom, while the remaining two presented with proptosis and fever with hepatomegaly, respectively. By contrast, in the AECD cohort, the most common initial symptom was bone pain (31.3%), followed in descending order by polyuria/polydipsia (23.9%), fever (17.9%), proptosis (14.9%), skin rash (13.4%), and anorexia (11.9%). Patients with PECD exhibited distinct patterns of organ involvement (Fig. 2 ), with lower rates of bone involvement (60.0% vs. 97.0%; P = 0.022) and cardiac/large vessel involvement (0% vs. 65.7%; P = 0.007), compared with the adult population. Although pediatric-onset patients demonstrated higher involvement rates in non-hypothalamic/pituitary central nervous system (CNS) regions (100% vs. 49.3%, P = 0.056) and hypothalamic/pituitary regions (60% vs. 35.8%, P = 0.357), these differences did not reach statistical significance. Conversely, lower involvement rates were observed in patients with PECD for the lung ( P > 0.999) and kidney/retroperitoneal space ( P = 0.182). Given that skeletal involvement is a characteristic feature of this disease, we conducted a detailed analysis of osseous manifestations. Firstly, we analyzed involvement by anatomical site. Patients with PECD demonstrated significantly lower appendicular skeletal involvement than patients with AECD [1/3 (33.3%) vs. 64/65 (98.5%); P = 0.004]. Craniofacial involvement was more frequent in the PECD cohort [3/3 (100%) vs. 34/65 (52.3%), P = 0.245]. Bony thorax [2/3 (66.7%) vs. 32/65 (49.2%); P > 0.999] and pelvis [1/3 (33.3%) vs. 29/65 (44.6%); P > 0.999] involvement rates were comparable to the adult cohort. Subsequently, we evaluated osseous lesions by imaging characteristics. Osteoblastic lesions predominated in both children (2/3, 66.7%) and adults (52/62, 83.9%; P = 0.505), while approximately one-third exhibited osteolytic lesions (pediatric: 1/3, adult: 22/62). Laboratory findings Comparative analysis of these two cohorts revealed significantly lower levels of CRP ( P = 0.005), ESR ( P = 0.035), fibrinogen ( P = 0.008), and SF ( P = 0.016) in the PECD group (Table 2 ). No significant differences were observed in hematologic parameters (including white blood cell counts, hemoglobin concentrations, and platelet counts) or IL-6, IL-8, IL-10, and tumor necrosis factor-α levels. Table 2 Comparison of laboratory data between the PECD and AECD cohorts at baseline PECD AECD P value WBC (×10 9 /L) 6.9 (6.1, 10.0) 6.9 (5.8, 11.9) 0.920 HB (g/L) 154.0 (141.5, 160.0) 125.0 (106.8, 136.3) 0.324 PLT (×10 9 /L) 357.0 (328.5, 445.0) 312.5 (229.0, 386.3) 0.397 CRP (mg/L) 0.3 (0.2, 0.6) 18.4 (7.0, 42.7) 0.005 ESR (mm/h) 3.0 (2.5, 5.0) 33.0 (19.5, 53.8) 0.035 FIB (g/L) 3.0 (2.9, 3.0) 4.3 (3.8, 5.5) 0.008 SF (ng/ml) 26.0 (17.5, 28.0) 112.0 (53.8, 173.8) 0.016 IL-6 (pg/ml) 2.9 (2.5, 4.8) 11.3 (6.2, 21.5) 0.240 IL-8 (pg/ml) 12.0 (11.5, 25.5) 21.5 (13.0, 63.5) 0.348 TNF-α (pg/ml) 11.6 (9.0, 13.7) 13.5 (9.6, 20.7) 0.504 Abbreviations: CRP C-reactive protein, ESR erythrocyte sedimentation rate, FIB fibrinogen, HB hemoglobin, IL interleukin, PLT platelet, SF serum ferritin, TNF tumor necrosis factor, WBC white blood cell With the exception of patient 4, all pediatric-onset patients tested for the BRAF V600E mutation were positive. Patient 4 was included based on the characteristic histopathological and clinical manifestations (including kidney/retroperitoneal space involvement) of ECD, despite the inability to perform genetic testing due to the extremely limited quantity of liver biopsy tissue obtained. In the AECD cohort, 63.5% of patients had positive BRAF V600E mutations. Imaging findings in the PECD cohort PECD demonstrated multisystem involvement, similar to AECD. Beyond the characteristic bilateral cortical sclerosis of lower limbs (Fig. 3 a) or osteoblastic lesions in other bones (Fig. 3 b), osteolytic lesions resembling those seen in LCH were also observed (Fig. 3 c). Among the five patients with PECD, CNS and pituitary involvement was observed at higher frequencies than in AECD, with imaging revealing enhancing mass lesions in the meninges, pineal region, cerebellum, and pituitary stalk (Figs. 3 d and e). Hepatic involvement was exclusively observed in pediatric patients, manifesting radiologically as hepatomegaly and ribbon-like lesions tracking portal tracts (Fig. 3 f). Treatment and outcomes Among 5 patients with PECD, 2 received BRAF kinase inhibitors (BRAFi; +/- corticosteroids), 2 received interferon-α-2a (IFNα-2a; +/- corticosteroids), and 1 underwent active surveillance after surgery. In the AECD cohort (during initial treatment), 52 patients received IFNα therapy, 9 received BRAF inhibitor therapy, 3 received glucocorticoid therapy, 2 received cytarabine + IFNα therapy, and 1 underwent active surveillance after surgery. Compared with the AECD cohort, patients with PECD showed a trend toward higher 8-year PFS (80.0% vs. 35.0%; Fig. 4 a) and OS (100.0% vs. 80.5%; Fig. 4 b) rates. The detailed treatment and outcome of all children were as follows: Patient 1: Treated with prednisone 1 mg/kg and dabrafenib 75 mg twice daily (bid). Disease remained stable during steroid tapering. Dabrafenib dosage was adjusted to 75 mg bid for 9 months, to 75 mg once daily (qd) for 9 months, and then to 75 mg every other day (qod) for maintenance. No disease progression, recurrence, or drug-related adverse events (AEs) were observed during 40.6-month follow-up. At last follow-up (age 15 years), the treatment response was assessed as complete response (CR). Patient 2: Received vemurafenib monotherapy for 1.6 years. Disease relapsed 8 months post-cessation (bilateral ankle pain; new bone and cauda equina lesions, and progressive intracranial lesions on PET-CT). Laboratory assessment revealed an elevated CRP level of 32.13 mg/L, while ESR, SF, and cytokine levels remained within normal limits. Dabrafenib (from 100 mg bid, to 50 mg bid, and then to 50 mg qd) induced gradual remission. Treatment-related adverse events (Common Terminology Criteria for Adverse Events version 5.0) included grade 1 rash, hyperkeratosis, and arthralgia. The final response assessment at last follow-up (age 16 years) documented partial response (PR). Patient 3: Treated with IFNα-2a 1 million units qd and prednisone 15 mg qd. Steroids were tapered over 5.4 years; IFNα-2a continued for 5 years with concurrent recombinant human growth hormone therapy for 3 years. PR criteria were met at end-of-study evaluation (age 13 years). Patient 4: Treated with IFNα-2a 1 million units thrice weekly for several years (exact duration unspecified). The patient was alive at the last documented follow-up in December 2022 but was subsequently lost to follow-up. Patient 5: Received no ECD-specific therapy. Brain imaging showed stable intracranial lesions (stable disease, SD), but the patient had persistent neurocognitive deficits (impaired language expression, reading comprehension, logical reasoning, and attention span). No new lesions had developed by the last follow-up assessment (age 12 years). Discussion This study compared ethnically matched pediatric and adult ECD cohorts from the same institution. Compared with the study by Vaglio et al. [ 11 ], our study provides a more focused and comprehensive analysis of the differential characteristics between pediatric and adult patients. The single-center design and racially homogeneous cohorts enhance comparability. The median time from symptom onset to diagnosis was 8.9 months, consistent with published research but shorter than that in patients with AECD (27.1 months). The shorter diagnostic interval may be attributed to distinct patterns of organ involvement and more overt symptomatology in children compared to adults. Alternatively, it may reflect greater parental vigilance regarding child health and prompt medical attention-seeking. Furthermore, given the disease's significant impact on pediatric growth, development, and long-term health, enhanced recognition by pediatricians remains crucial to further expedite diagnosis and reduce misdiagnoses. Regarding initial manifestations, a key difference from adult patients was the predominance of polyuria/polydipsia as the most frequent presenting symptom in children. In contrast, bone pain—the most common initial symptom in adults—rarely served as the presenting complaint in pediatric cases, a factor that likely contributes to misdiagnosis in children. CNS (excluding hypothalamic/pituitary) and hypothalamic/pituitary represented the two most frequently involved sites in patients with PECD, accounting for 100% and 60% of cases, respectively. In the combined pediatric-adult cohort studied by Julien Haroche et al., CNS involvement conferred a 2.51-fold increased mortality risk as an independent predictor of poor prognosis [ 10 ]. Given the unique physiological demands of growth and development in childhood, lesions in this region may disrupt the secretion of endocrine hormones, primarily growth hormone, which are essential for normal growth and development. Therefore, early diagnosis and timely initiation of hormone replacement therapy are particularly critical for pediatric patients compared to adults. It is noteworthy that although patient 5 presented with isolated CNS involvement and lacked typical ECD clinical manifestations, according to the consensus recommendations, patients with positive BRAF V600E mutation should be strongly considered to belong to the ECD spectrum rather than juvenile xanthogranuloma [ 2 ]. Similar cases have also been reported in the study by Picarsic et al. [ 13 ]. Pediatric patients appear to have a lower prevalence of bone involvement compared to adult patients, with less frequent reporting of bone pain. Furthermore, detailed subgroup analysis revealed that pediatric patients had substantially lower rates of appendicular skeletal involvement compared to adults, while craniofacial bone involvement showed a higher trend. Osteolytic bone lesions were observed in both pediatric and adult patients with ECD. This suggests that many patients with PECD may lack bilateral symmetric osteosclerosis typically observed in AECD. Therefore, when craniofacial bone lesions or osteolytic lesions are identified in children, pediatricians should consider PECD in the differential diagnosis alongside LCH, the most common histiocytic disorder in children. Pediatric-onset patients exhibited reduced rates of kidney/retroperitoneal space and cardiac/large vessel involvement compared to adults, consistent with findings reported by Vaglio et al. [ 11 ]. The underlying etiology remains unclear, and this distinct pattern poses challenges in clinical diagnosis. This study identified significantly lower inflammatory markers—including CRP, ESR, and SF—in the PECD cohort compared to adult patients. Although ECD is currently classified as a neoplasm, inflammatory responses are recognized to play a crucial role in its pathogenesis [ 14 ]. Additionally, pediatric patients demonstrated a trend toward higher PFS and OS rates compared to adult patients. This observation may potentially be attributed to the relatively less active inflammatory response and slower disease activity in pediatric populations. Notably, the only relapsed PECD case in our center (patient 2) exhibited a marked elevation in CRP at disease recurrence. Similarly, some studies have reported elevated serum CRP levels in more than 80% of ECD cohort including pediatric patients [ 10 , 12 ]. These findings collectively suggest that inflammatory markers such as CRP may serve as potential indicators of disease activity, requiring close monitoring. The discovery of MAPK pathway gene mutations (particularly BRAF V600E ) in patients with ECD has led to the current hypothesis that somatic mutations of precursor cells underlie its pathogenesis [ 2 ]. Drawing parallels to the pathogenic model of pediatric LCH, we postulate that the developmental timing or cellular context of somatic mutations in PECD may differ from AECD, potentially contributing to distinct clinical manifestations and organ involvement [ 15 ]. This hypothesis warrants validation through in vivo/ex vivo models. MAPK pathway inhibitors, such as BRAF kinase inhibitors (e.g., vemurafenib, dabrafenib), demonstrate promising therapeutic efficacy with generally safe and manageable adverse events [ 16 ]. However, post-discontinuation relapse remains a critical concern, as exemplified by patient 2. Whether low-dose maintenance therapy could mitigate relapse risk remains unclear, necessitating large-scale multicenter clinical trials for further exploration. Notably, patient 5, who received no treatment after surgery, exhibited stable intracranial lesions radiologically but developed neurodegenerative-like symptoms. This highlights that clinical decision-making should not rely solely on imaging findings. Due to the current lack of randomized controlled trials comparing different therapeutic regimens for ECD, the comparative efficacy of corticosteroids, IFNα, and targeted therapies remains inconclusive. Several studies suggest that BRAF and/or MEK inhibitors could be prioritized as first-line therapy for patients with CNS involvement [ 17 ]. Compared to adult patients, pediatric patients appear to have better survival outcomes. However, as CNS involvement is more prevalent in children than in adults, pediatric patients not receiving ECD-targeted therapy seem to be at higher risk of developing persistent neurological sequelae, including cognitive impairment, attention deficits, central diabetes insipidus, etc. Notably, the study by Vaglio et al. suggests that the patient with exclusively bone involvement may have a favorable outcome even without ECD-targeted therapy (with follow-up duration extending to 60 months) [ 11 ]. In conclusion, PECD and AECD exhibit distinct differences in clinical manifestations, predominant systems of involvement, and inflammatory response intensity. In pediatric-onset patients, CNS and hypothalamic/pituitary involvement may also represent one of the characteristic clinical manifestations of ECD. However, this feature has not been mentioned in the consensus recommendations for AECD. Current therapeutic approaches for PECD remain heterogeneous. MAPK pathway-targeted therapies show potential clinical utility; however, relapse following treatment cessation persists as a notable limitation. Inflammatory markers such as CRP may serve as potential indicators of disease activity, requiring close monitoring. The observed survival advantage in pediatric patients compared to adults may be attributable to less inflammatory activation. Future investigations should focus on establishing in vivo/ex vivo disease models and conducting large-scale clinical trials to elucidate pathogenic mechanisms and optimize therapeutic strategies. Abbreviations 18F-FDG PET-CT 18F-fluorodeoxyglucose positron emission tomography-computed tomography AECD adult-onset Erdheim-Chester Disease BRAFi BRAF kinase inhibitors CNS central nervous system CR complete response CRP C-reactive protein ECD Erdheim-Chester Disease ESR erythrocyte sedimentation rate IFN interferon IHC immunohistochemistry IL interleukin IQR interquartile range LCH Langerhans cell histiocytosis MAPK mitogen-activated protein kinase OS overall survival PCR polymerase chain reaction PECD pediatric-onset Erdheim-Chester Disease PFS progression-free survival PR partial response SD stable disease SF serum ferritin Declarations Competing Interests The authors have no relevant financial or non-financial interests to disclose. Ethics approval This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Peking Union Medical College Hospital (I-24PJ0015). Consent to participate Written informed consent was obtained from the parents or legal guardians of the participating children. Consent to publish The authors affirm that human research participants provided informed consent for publication of the images in figures. Funding This work was supported by the CAMS Innovation Fund for Medical Sciences (2022-I2M-C&T-B-009), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-040, 2022-PUMCH-B-079) and Peking Union Medical College Hospital Research Funding for Postdoc (kyfyjj202414). Author Contribution Y.Y. and ZC.L. drafted the manuscript. ZZ.L. and XX.C. collected and analyzed the clinical data of AECD. JY.Y. and WH.Z. reviewed and interpreted the radiologic imaging. J.X., XX.C. and WH.Z. participated in the study concept and design, revised this article critically for important intellectual content, and final approval of the version to be published. 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Blood 135:1319–1331. https://doi.org/10.1182/blood.2019000934 Doke R, Lokhande R, Chande K, Vinchurkar K, Prajapati BG (2025) Recent advances in therapeutic strategies of Erdheim-Chester disease. Naunyn Schmiedebergs Arch Pharmacol 398:6407–6428. https://doi.org/10.1007/s00210-024-03769-2 Cohen Aubart F, Idbaih A, Emile JF, Amoura Z, Abdel-Wahab O, Durham BH, Haroche J, Diamond EL (2021) Histiocytosis and the nervous system: from diagnosis to targeted therapies. Neuro Oncol 23:1433–1446. https://doi.org/10.1093/neuonc/noab107 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8300528","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":561096996,"identity":"8ba70e5c-0c50-4fe6-8a7b-d546e83e186b","order_by":0,"name":"Ying Yang","email":"","orcid":"","institution":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Yang","suffix":""},{"id":561096997,"identity":"298160b5-043b-4508-bd5a-ba6dede36b16","order_by":1,"name":"Zi-Chao Lyu","email":"","orcid":"","institution":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zi-Chao","middleName":"","lastName":"Lyu","suffix":""},{"id":561096998,"identity":"85c76323-1a81-4534-8132-71fbcdf1c7d7","order_by":2,"name":"Zheng-Zheng Liu","email":"","orcid":"","institution":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Zheng-Zheng","middleName":"","lastName":"Liu","suffix":""},{"id":561097002,"identity":"ea533399-aa43-405d-95fd-e88158c7fd7f","order_by":3,"name":"Zhuo Li","email":"","orcid":"","institution":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical 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Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yue-Lun","middleName":"","lastName":"Zhang","suffix":""},{"id":561097014,"identity":"eb8676a0-4e64-4582-824c-13c8a8715d0a","order_by":7,"name":"Xin-Xin Cao","email":"","orcid":"","institution":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Xin-Xin","middleName":"","lastName":"Cao","suffix":""},{"id":561097016,"identity":"50c72fd1-6cd3-4bba-a349-b05f1d1eb6fd","order_by":8,"name":"Wei-Hong Zhang","email":"","orcid":"","institution":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Wei-Hong","middleName":"","lastName":"Zhang","suffix":""},{"id":561097018,"identity":"2d43a4d0-742f-4a53-8cab-c6e7bef8232e","order_by":9,"name":"Juan Xiao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYDACZiCWAGJ+EIexgRQtkg1Ea4EBgwPEajE4zvzwgWWbXZ7x7R7TDT93MMibE9Ii2cxmbCDZllxsdueM2c3eMwyGOwnZxM/MYCYh2cacuO1GjtltxjaGBLAL8QE2ZvZvQC31iZtnEKuFn5kHZMvhxA0SxGqRbOYpNpA4dzxxxp1jZTd72yQMNxDSYnD++MbHEmXVif2zm7fd+NlmI0/QFhBgBkUlOD5hJEHA+IEExaNgFIyCUTACAQB92D2/WabIBgAAAABJRU5ErkJggg==","orcid":"","institution":"Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Juan","middleName":"","lastName":"Xiao","suffix":""}],"badges":[],"createdAt":"2025-12-07 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12:30:50","extension":"html","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":98963,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8300528/v1/7943f79443c65b3db1f59190.html"},{"id":98752697,"identity":"5e4e7862-4467-4066-856e-9e97fcfba8a6","added_by":"auto","created_at":"2025-12-22 09:18:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":785006,"visible":true,"origin":"","legend":"\u003cp\u003eHistopathological findings and PCR testing result for \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e \u003cstrong\u003ea\u003c/strong\u003e Sellar mass. Hematoxylin-eosin staining shows increased fibrous tissue with infiltration of histiocytes and lymphocytes (20×). \u003cstrong\u003eb\u003c/strong\u003e IHC staining for CD68 was positive. \u003cstrong\u003ec\u003c/strong\u003e and \u003cstrong\u003ed\u003c/strong\u003e IHC staining for CD1a and S100, respectively, was negative. \u003cstrong\u003ee\u003c/strong\u003e PCR testing for the \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutation was positive (threshold cycle value was 17).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8300528/v1/405d402b46d3685a49edff5d.png"},{"id":98779121,"identity":"89f1e2fa-2358-4146-921a-c2e0c504ce4a","added_by":"auto","created_at":"2025-12-22 12:29:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":365088,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic and proportional representation of predominant organ involvement patterns in patients with PECD versus AECD\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8300528/v1/a4bcec47beba9cd680b2cca8.png"},{"id":98777187,"identity":"80af047a-3eb0-4a80-bca5-4daede073bb5","added_by":"auto","created_at":"2025-12-22 12:25:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1554917,"visible":true,"origin":"","legend":"\u003cp\u003eImaging manifestations of the patients with PECD (red arrows) \u003cstrong\u003ea\u003c/strong\u003e Bilateral cortical sclerosis of the tibiae and fibulae (patient 3). \u003cstrong\u003eb\u003c/strong\u003eOsteosclerosis of the skull (patient 2). \u003cstrong\u003ec\u003c/strong\u003e Osteolysis of the rib (patient 1). \u003cstrong\u003ed\u003c/strong\u003e Nodular pituitary stalk mass (patient 3). \u003cstrong\u003ee\u003c/strong\u003e A mass in the pineal region and bilateral choroid plexus enlargement with intense enhancement (patient 1). \u003cstrong\u003ef\u003c/strong\u003e Hepatic ribbon-like lesions tracking the portal tracts (patient 4).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8300528/v1/8edc5c53b5c6719f96d6d177.png"},{"id":98752700,"identity":"724e0de1-1584-4d23-a923-d7f3dffc5157","added_by":"auto","created_at":"2025-12-22 09:18:04","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":476925,"visible":true,"origin":"","legend":"\u003cp\u003ePFS (\u003cstrong\u003ea\u003c/strong\u003e) and OS (\u003cstrong\u003eb\u003c/strong\u003e) in the PECD and AECD cohorts\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8300528/v1/79fab608a6861a4537b574f6.png"},{"id":99790669,"identity":"669871c7-b0fa-4fe6-85da-930ccbe68d6c","added_by":"auto","created_at":"2026-01-08 12:58:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3883303,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8300528/v1/f231194a-b3d2-4514-bc6a-475821d9a3bd.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Features and Prognosis of Pediatric-Onset Erdheim-Chester Disease Compared with an Adult-Onset Cohort from the Same Center","fulltext":[{"header":"What is Known ","content":"\u003cul\u003e\n \u003cli\u003eErdheim-Chester disease (ECD) is a rare histiocytic disorder predominantly affecting middle-aged adults. Currently published consensus on diagnosis and management is more applicable to adult patients.\u003c/li\u003e\n \u003cli\u003ePediatric-onset ECD are infrequently reported, and their clinical features are incompletely characterized.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eWhat is New\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cul start=\"50\"\u003e\n \u003cli\u003ePediatric-onset and adult-onset ECD differ in clinical manifestations and inflammation intensity.\u003c/li\u003e\n \u003cli\u003eThe consensus recommendations established for AECD may not be fully applicable to the pediatric population.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eErdheim-Chester disease (ECD) is a rare histiocytic disorder first identified in 1930. It is distinguished by a diverse clinical spectrum that ranges from mild, localized symptoms to severe, multisystem disease. The diagnosis is typically established through histopathological examination of lesional tissues, which demonstrates the presence of CD68-positive and CD1a-negative foamy histiocytes, in conjunction with characteristic clinical manifestations and genetic alterations of \u003cem\u003eBRAF\u003c/em\u003e mutations [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eECD predominantly affects middle-aged adults (AECD), with most diagnoses made between 46 and 56 years of age. Currently published consensus on diagnosis and management is more applicable to adult patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. However, pediatric-onset ECD (PECD) may exhibit unique clinical manifestations. Pediatricians' limited familiarity with PECD may contribute to misdiagnosis. PECD is particularly uncommon, with the first well-documented case reported in 1991 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This case demonstrated multisystem involvement (bone, pituitary, mediastinum, lung, kidney, etc.) and stabilized following surgical intervention and supportive care, suggesting that some patients with childhood-onset ECD may follow a benign course. The second pediatric case was not reported until 12 years later [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This patient also presented with multisystem involvement. Despite systemic chemotherapy using the Langerhans cell histiocytosis (LCH)-II protocol, intracranial lesions continued to progress. Subsequently, some cases were also refractory to corticosteroid combined with vinca alkaloid-based chemotherapy regimens [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Prior to the advent of targeted therapies, interferon α (IFNα) was the primary therapeutic approach [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Recent studies demonstrate that the mitogen-activated protein kinase (MAPK) pathway, particularly involving mutations in the \u003cem\u003eBRAF\u003c/em\u003e gene, plays an important role in the pathogenesis of ECD. BRAF kinase inhibitors (such as vemurafenib and dabrafenib) show promising therapeutic value [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA literature review indicates that PECD cases are predominantly documented in isolated case reports. Although the largest single-center series to date included five children within a combined adult-pediatric cohort, this study did not conduct rigorous comparative analyses of phenotypic distinctions between pediatric and adult populations [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A recent multicenter study by Vaglio et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] included patients with PECD (n\u0026thinsp;=\u0026thinsp;13) and mixed ECD/LCH from 23 institutions. This study inadequately addresses the clinical differences between patients with PECD and AECD. However, key limitations\u0026mdash;including ethnic heterogeneity, variable pathology/laboratory standards, and insufficient laboratory data\u0026mdash;compromised the analysis. These limitations precluded an in-depth analysis of the distinctive clinical manifestations, laboratory/imaging characteristics, treatment responses, and outcomes between PECD and AECD. Managing PECD based on data and experiences derived from AECD cohorts may not represent the optimal approach. Our study addresses this gap through a comparative analysis of PECD and ethnically matched AECD from the same center. This approach aims to delineate disease-specific features and enhance pediatricians' understanding of PECD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and study design\u003c/h2\u003e \u003cp\u003eThis retrospective study was conducted at Peking Union Medical College Hospital (PUMCH) and included patients aged less than 18 years who were diagnosed with PECD as the observation group between July 2012 and July 2022. The diagnosis of ECD in these patients was established based on characteristic histopathological findings (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea-d) independently confirmed by two pathologists according to the 2017 World Health Organization classification criteria (negative staining for CD1a, S100, or CD207 excludes mixed LCH/ECD). Additionally, patients were required to meet at least one of the following two criteria: (1) presence of at least one typical clinical manifestation of ECD; (2) positive detection of \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee). For comparative analysis, patients with AECD from the same period were included from our previously described cohort at the same center as the control group [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical, laboratory, radiologic imaging and genetic data\u003c/h3\u003e\n\u003cp\u003eIn this study, comprehensive clinical data were collected, including detailed demographic information (age, gender, etc.), thorough documentation of clinical presentations, and routine hematological tests such as white blood cell count, neutrophil count, and platelet count. Additionally, a panel of inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum ferritin (SF), fibrinogen, and cytokines (interleukin [IL]-6, IL-8, IL-10, and tumor necrosis factor-α) was evaluated.\u003c/p\u003e \u003cp\u003eRadiological examinations, including radiography, high-resolution computed tomography, magnetic resonance imaging, bone scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT), were independently reviewed and interpreted by two radiologists.\u003c/p\u003e \u003cp\u003eGenetic analysis for the \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutation was performed by polymerase chain reaction (PCR) on the pathological tissue in pediatric patients. In adults, the \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutation was detected by next-generation sequencing, PCR, or immunohistochemistry (IHC), as previously described [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eFollow-up\u003c/h3\u003e\n\u003cp\u003eAll patients were followed up through clinic visits or by telephone. The last follow-up time for PECD and AECD was December 31, 2024. Overall survival (OS) and progression-free survival (PFS) were used to assess patient outcomes. OS was defined as the duration from the date of ECD diagnosis to either the date of death or the last follow-up appointment, whichever occurred first. PFS was calculated from the date of diagnosis to the first occurrence of disease progression, relapse, or death from any cause, whichever came first. Treatment response was evaluated by modified PET Response Criteria in Solid Tumors using 18F-FDG PET-CT and cranial/pituitary magnetic resonance imaging with contrast [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics version 23.0. Non-normally distributed continuous variables were presented as median (IQR) and compared using the Mann-Whitney U test. Categorical data were expressed as numbers (percentages). Categorical variables were compared by chi-square test or Fisher's exact test as appropriate. Survival curves were estimated using the Kaplan-Meier method, and the log-rank test was used to compare the groups.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGeneral information\u003c/h2\u003e \u003cp\u003eA total of 5 children with PECD were included from our center (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), comprising 4 male patients and 1 female patient, with a median age at diagnosis of 8.0 years (range: 4.4\u0026ndash;12.1). The adult cohort comprised 71 patients with AECD. Four additional patients were excluded during follow-up due to concurrent other histiocytic disorders in three patients or acute myeloid leukemia in one patient. A total of 67 patients with AECD (control group) were ultimately included.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of the single-center PECD cohort\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInvolvement\u0026nbsp;systems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFollow-up period (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHeight\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSequela\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 1 (12.1y, M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebone, CNS, hypothalamic/pituitary, gallbladder, descending duodenum, lung and pleura\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprednisone\u0026thinsp;+\u0026thinsp;dabrafenib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP3-10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 2 (10.4y, M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebone, CNS, hypothalamic/pituitary, lung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003evemurafenib\u0026rarr; dabrafenib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e49.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCR\u0026rarr;relapse\u0026rarr;PR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP25-50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 3 (5.1y, M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebone, skin, CNS, hypothalamic/pituitary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eprednisone\u0026thinsp;+\u0026thinsp;IFNα-2a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e101.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;P3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003epanhypopituitarism, osteochondral dysplasia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 4 (4.4y, M)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCNS, lung, liver, kidney/retroperitoneal space\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIFNα-2a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e91.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePR (loss to follow-up after December 2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003elost to follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003esensorineural hearing loss\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatient 5 (8.0y, F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eobservation after lesion resection surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP50-75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ecognitive impairment, decreased attention\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eAbbreviations: CNS\u003c/em\u003e central nervous system, \u003cem\u003eCR\u003c/em\u003e complete response, \u003cem\u003eDI\u003c/em\u003e diabetes insipidus, \u003cem\u003eF\u003c/em\u003e female, \u003cem\u003eIFN\u003c/em\u003e interferon, \u003cem\u003eM\u003c/em\u003e male, \u003cem\u003ePR\u003c/em\u003e partial response, \u003cem\u003eSD\u003c/em\u003e stable disease\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCompared with the AECD cohort, the PECD cohort showed no statistically significant difference in gender distribution (males accounted for 80% vs. 46.3%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.193). The median time from symptom onset to definitive diagnosis was 8.9 months (IQR 5.2\u0026ndash;36.2) in the PECD cohort, shorter than that in patients with AECD (27.1 months, IQR 10.1\u0026ndash;56.5), though not statistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.308).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical manifestations\u003c/h3\u003e\n\u003cp\u003eRegarding initial presenting symptoms, among patients with PECD, three cases (60%) manifested polyuria/polydipsia as the primary symptom, while the remaining two presented with proptosis and fever with hepatomegaly, respectively. By contrast, in the AECD cohort, the most common initial symptom was bone pain (31.3%), followed in descending order by polyuria/polydipsia (23.9%), fever (17.9%), proptosis (14.9%), skin rash (13.4%), and anorexia (11.9%).\u003c/p\u003e \u003cp\u003ePatients with PECD exhibited distinct patterns of organ involvement (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), with lower rates of bone involvement (60.0% vs. 97.0%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) and cardiac/large vessel involvement (0% vs. 65.7%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), compared with the adult population. Although pediatric-onset patients demonstrated higher involvement rates in non-hypothalamic/pituitary central nervous system (CNS) regions (100% vs. 49.3%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.056) and hypothalamic/pituitary regions (60% vs. 35.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.357), these differences did not reach statistical significance. Conversely, lower involvement rates were observed in patients with PECD for the lung (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.999) and kidney/retroperitoneal space (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.182).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven that skeletal involvement is a characteristic feature of this disease, we conducted a detailed analysis of osseous manifestations. Firstly, we analyzed involvement by anatomical site. Patients with PECD demonstrated significantly lower appendicular skeletal involvement than patients with AECD [1/3 (33.3%) vs. 64/65 (98.5%); \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004]. Craniofacial involvement was more frequent in the PECD cohort [3/3 (100%) vs. 34/65 (52.3%), \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.245]. Bony thorax [2/3 (66.7%) vs. 32/65 (49.2%); \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.999] and pelvis [1/3 (33.3%) vs. 29/65 (44.6%); \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.999] involvement rates were comparable to the adult cohort. Subsequently, we evaluated osseous lesions by imaging characteristics. Osteoblastic lesions predominated in both children (2/3, 66.7%) and adults (52/62, 83.9%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.505), while approximately one-third exhibited osteolytic lesions (pediatric: 1/3, adult: 22/62).\u003c/p\u003e\n\u003ch3\u003eLaboratory findings\u003c/h3\u003e\n\u003cp\u003eComparative analysis of these two cohorts revealed significantly lower levels of CRP (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), ESR (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035), fibrinogen (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), and SF (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) in the PECD group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). No significant differences were observed in hematologic parameters (including white blood cell counts, hemoglobin concentrations, and platelet counts) or IL-6, IL-8, IL-10, and tumor necrosis factor-α levels.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of laboratory data between the PECD and AECD cohorts at baseline\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePECD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAECD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.9\u0026nbsp;(6.1,\u0026nbsp;10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.9 (5.8, 11.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.920\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHB (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e154.0\u0026nbsp;(141.5,\u0026nbsp;160.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e125.0 (106.8, 136.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.324\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e357.0\u0026nbsp;(328.5,\u0026nbsp;445.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e312.5 (229.0, 386.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.397\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (mg/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.3\u0026nbsp;(0.2,\u0026nbsp;0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18.4 (7.0, 42.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR (mm/h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.0\u0026nbsp;(2.5,\u0026nbsp;5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33.0 (19.5, 53.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFIB (g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.0\u0026nbsp;(2.9,\u0026nbsp;3.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.3 (3.8, 5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSF (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26.0\u0026nbsp;(17.5,\u0026nbsp;28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e112.0 (53.8, 173.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-6 (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.9\u0026nbsp;(2.5,\u0026nbsp;4.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.3 (6.2, 21.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.240\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIL-8 (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12.0\u0026nbsp;(11.5,\u0026nbsp;25.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21.5 (13.0, 63.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.348\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTNF-α (pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11.6\u0026nbsp;(9.0,\u0026nbsp;13.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13.5 (9.6, 20.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAbbreviations: CRP\u003c/em\u003e C-reactive protein, \u003cem\u003eESR\u003c/em\u003e erythrocyte sedimentation rate, \u003cem\u003eFIB\u003c/em\u003e fibrinogen, \u003cem\u003eHB\u003c/em\u003e hemoglobin, \u003cem\u003eIL\u003c/em\u003e interleukin, \u003cem\u003ePLT\u003c/em\u003e platelet, \u003cem\u003eSF\u003c/em\u003e serum ferritin, \u003cem\u003eTNF\u003c/em\u003e tumor necrosis factor, \u003cem\u003eWBC\u003c/em\u003e white blood cell\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWith the exception of patient 4, all pediatric-onset patients tested for the \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutation were positive. Patient 4 was included based on the characteristic histopathological and clinical manifestations (including kidney/retroperitoneal space involvement) of ECD, despite the inability to perform genetic testing due to the extremely limited quantity of liver biopsy tissue obtained. In the AECD cohort, 63.5% of patients had positive \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutations.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eImaging findings in the PECD cohort\u003c/h2\u003e \u003cp\u003ePECD demonstrated multisystem involvement, similar to AECD. Beyond the characteristic bilateral cortical sclerosis of lower limbs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea) or osteoblastic lesions in other bones (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb), osteolytic lesions resembling those seen in LCH were also observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). Among the five patients with PECD, CNS and pituitary involvement was observed at higher frequencies than in AECD, with imaging revealing enhancing mass lesions in the meninges, pineal region, cerebellum, and pituitary stalk (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed and e). Hepatic involvement was exclusively observed in pediatric patients, manifesting radiologically as hepatomegaly and ribbon-like lesions tracking portal tracts (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ef).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTreatment and outcomes\u003c/h2\u003e \u003cp\u003eAmong 5 patients with PECD, 2 received BRAF kinase inhibitors (BRAFi; +/- corticosteroids), 2 received interferon-α-2a (IFNα-2a; +/- corticosteroids), and 1 underwent active surveillance after surgery. In the AECD cohort (during initial treatment), 52 patients received IFNα therapy, 9 received BRAF inhibitor therapy, 3 received glucocorticoid therapy, 2 received cytarabine\u0026thinsp;+\u0026thinsp;IFNα therapy, and 1 underwent active surveillance after surgery. Compared with the AECD cohort, patients with PECD showed a trend toward higher 8-year PFS (80.0% vs. 35.0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea) and OS (100.0% vs. 80.5%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb) rates.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe detailed treatment and outcome of all children were as follows:\u003c/p\u003e \u003cp\u003ePatient 1: Treated with prednisone 1 mg/kg and dabrafenib 75 mg twice daily (bid). Disease remained stable during steroid tapering. Dabrafenib dosage was adjusted to 75 mg bid for 9 months, to 75 mg once daily (qd) for 9 months, and then to 75 mg every other day (qod) for maintenance. No disease progression, recurrence, or drug-related adverse events (AEs) were observed during 40.6-month follow-up. At last follow-up (age 15 years), the treatment response was assessed as complete response (CR).\u003c/p\u003e \u003cp\u003ePatient 2: Received vemurafenib monotherapy for 1.6 years. Disease relapsed 8 months post-cessation (bilateral ankle pain; new bone and cauda equina lesions, and progressive intracranial lesions on PET-CT). Laboratory assessment revealed an elevated CRP level of 32.13 mg/L, while ESR, SF, and cytokine levels remained within normal limits. Dabrafenib (from 100 mg bid, to 50 mg bid, and then to 50 mg qd) induced gradual remission. Treatment-related adverse events (Common Terminology Criteria for Adverse Events version 5.0) included grade 1 rash, hyperkeratosis, and arthralgia. The final response assessment at last follow-up (age 16 years) documented partial response (PR).\u003c/p\u003e \u003cp\u003ePatient 3: Treated with IFNα-2a 1\u0026nbsp;million units qd and prednisone 15 mg qd. Steroids were tapered over 5.4 years; IFNα-2a continued for 5 years with concurrent recombinant human growth hormone therapy for 3 years. PR criteria were met at end-of-study evaluation (age 13 years).\u003c/p\u003e \u003cp\u003ePatient 4: Treated with IFNα-2a 1\u0026nbsp;million units thrice weekly for several years (exact duration unspecified). The patient was alive at the last documented follow-up in December 2022 but was subsequently lost to follow-up.\u003c/p\u003e \u003cp\u003ePatient 5: Received no ECD-specific therapy. Brain imaging showed stable intracranial lesions (stable disease, SD), but the patient had persistent neurocognitive deficits (impaired language expression, reading comprehension, logical reasoning, and attention span). No new lesions had developed by the last follow-up assessment (age 12 years).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study compared ethnically matched pediatric and adult ECD cohorts from the same institution. Compared with the study by Vaglio et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], our study provides a more focused and comprehensive analysis of the differential characteristics between pediatric and adult patients. The single-center design and racially homogeneous cohorts enhance comparability.\u003c/p\u003e \u003cp\u003eThe median time from symptom onset to diagnosis was 8.9 months, consistent with published research but shorter than that in patients with AECD (27.1 months). The shorter diagnostic interval may be attributed to distinct patterns of organ involvement and more overt symptomatology in children compared to adults. Alternatively, it may reflect greater parental vigilance regarding child health and prompt medical attention-seeking. Furthermore, given the disease's significant impact on pediatric growth, development, and long-term health, enhanced recognition by pediatricians remains crucial to further expedite diagnosis and reduce misdiagnoses.\u003c/p\u003e \u003cp\u003eRegarding initial manifestations, a key difference from adult patients was the predominance of polyuria/polydipsia as the most frequent presenting symptom in children. In contrast, bone pain\u0026mdash;the most common initial symptom in adults\u0026mdash;rarely served as the presenting complaint in pediatric cases, a factor that likely contributes to misdiagnosis in children.\u003c/p\u003e \u003cp\u003eCNS (excluding hypothalamic/pituitary) and hypothalamic/pituitary represented the two most frequently involved sites in patients with PECD, accounting for 100% and 60% of cases, respectively. In the combined pediatric-adult cohort studied by Julien Haroche et al., CNS involvement conferred a 2.51-fold increased mortality risk as an independent predictor of poor prognosis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Given the unique physiological demands of growth and development in childhood, lesions in this region may disrupt the secretion of endocrine hormones, primarily growth hormone, which are essential for normal growth and development. Therefore, early diagnosis and timely initiation of hormone replacement therapy are particularly critical for pediatric patients compared to adults. It is noteworthy that although patient 5 presented with isolated CNS involvement and lacked typical ECD clinical manifestations, according to the consensus recommendations, patients with positive \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e mutation should be strongly considered to belong to the ECD spectrum rather than juvenile xanthogranuloma [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Similar cases have also been reported in the study by Picarsic et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePediatric patients appear to have a lower prevalence of bone involvement compared to adult patients, with less frequent reporting of bone pain. Furthermore, detailed subgroup analysis revealed that pediatric patients had substantially lower rates of appendicular skeletal involvement compared to adults, while craniofacial bone involvement showed a higher trend. Osteolytic bone lesions were observed in both pediatric and adult patients with ECD. This suggests that many patients with PECD may lack bilateral symmetric osteosclerosis typically observed in AECD. Therefore, when craniofacial bone lesions or osteolytic lesions are identified in children, pediatricians should consider PECD in the differential diagnosis alongside LCH, the most common histiocytic disorder in children. Pediatric-onset patients exhibited reduced rates of kidney/retroperitoneal space and cardiac/large vessel involvement compared to adults, consistent with findings reported by Vaglio et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The underlying etiology remains unclear, and this distinct pattern poses challenges in clinical diagnosis.\u003c/p\u003e \u003cp\u003eThis study identified significantly lower inflammatory markers\u0026mdash;including CRP, ESR, and SF\u0026mdash;in the PECD cohort compared to adult patients. Although ECD is currently classified as a neoplasm, inflammatory responses are recognized to play a crucial role in its pathogenesis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Additionally, pediatric patients demonstrated a trend toward higher PFS and OS rates compared to adult patients. This observation may potentially be attributed to the relatively less active inflammatory response and slower disease activity in pediatric populations. Notably, the only relapsed PECD case in our center (patient 2) exhibited a marked elevation in CRP at disease recurrence. Similarly, some studies have reported elevated serum CRP levels in more than 80% of ECD cohort including pediatric patients [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. These findings collectively suggest that inflammatory markers such as CRP may serve as potential indicators of disease activity, requiring close monitoring.\u003c/p\u003e \u003cp\u003eThe discovery of MAPK pathway gene mutations (particularly \u003cem\u003eBRAF\u003c/em\u003e\u003csup\u003eV600E\u003c/sup\u003e) in patients with ECD has led to the current hypothesis that somatic mutations of precursor cells underlie its pathogenesis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Drawing parallels to the pathogenic model of pediatric LCH, we postulate that the developmental timing or cellular context of somatic mutations in PECD may differ from AECD, potentially contributing to distinct clinical manifestations and organ involvement [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. This hypothesis warrants validation through in vivo/ex vivo models. MAPK pathway inhibitors, such as BRAF kinase inhibitors (e.g., vemurafenib, dabrafenib), demonstrate promising therapeutic efficacy with generally safe and manageable adverse events [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, post-discontinuation relapse remains a critical concern, as exemplified by patient 2. Whether low-dose maintenance therapy could mitigate relapse risk remains unclear, necessitating large-scale multicenter clinical trials for further exploration. Notably, patient 5, who received no treatment after surgery, exhibited stable intracranial lesions radiologically but developed neurodegenerative-like symptoms. This highlights that clinical decision-making should not rely solely on imaging findings. Due to the current lack of randomized controlled trials comparing different therapeutic regimens for ECD, the comparative efficacy of corticosteroids, IFNα, and targeted therapies remains inconclusive. Several studies suggest that BRAF and/or MEK inhibitors could be prioritized as first-line therapy for patients with CNS involvement [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCompared to adult patients, pediatric patients appear to have better survival outcomes. However, as CNS involvement is more prevalent in children than in adults, pediatric patients not receiving ECD-targeted therapy seem to be at higher risk of developing persistent neurological sequelae, including cognitive impairment, attention deficits, central diabetes insipidus, etc. Notably, the study by Vaglio et al. suggests that the patient with exclusively bone involvement may have a favorable outcome even without ECD-targeted therapy (with follow-up duration extending to 60 months) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn conclusion, PECD and AECD exhibit distinct differences in clinical manifestations, predominant systems of involvement, and inflammatory response intensity. In pediatric-onset patients, CNS and hypothalamic/pituitary involvement may also represent one of the characteristic clinical manifestations of ECD. However, this feature has not been mentioned in the consensus recommendations for AECD. Current therapeutic approaches for PECD remain heterogeneous. MAPK pathway-targeted therapies show potential clinical utility; however, relapse following treatment cessation persists as a notable limitation. Inflammatory markers such as CRP may serve as potential indicators of disease activity, requiring close monitoring. The observed survival advantage in pediatric patients compared to adults may be attributable to less inflammatory activation. Future investigations should focus on establishing in vivo/ex vivo disease models and conducting large-scale clinical trials to elucidate pathogenic mechanisms and optimize therapeutic strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e18F-FDG PET-CT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e18F-fluorodeoxyglucose positron emission tomography-computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAECD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eadult-onset Erdheim-Chester Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBRAFi\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBRAF kinase inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecentral nervous system\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomplete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eECD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eErdheim-Chester Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eerythrocyte sedimentation rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIFN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterferon\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIHC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmunohistochemistry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterleukin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLCH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLangerhans cell histiocytosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMAPK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emitogen-activated protein kinase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epolymerase chain reaction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePECD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epediatric-onset Erdheim-Chester Disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estable disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserum ferritin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Peking Union Medical College Hospital (I-24PJ0015).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from the parents or legal guardians of the participating children.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to publish\u003c/strong\u003e \u003cp\u003e The authors affirm that human research participants provided informed consent for publication of the images in figures.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the CAMS Innovation Fund for Medical Sciences (2022-I2M-C\u0026amp;T-B-009), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-040, 2022-PUMCH-B-079) and Peking Union Medical College Hospital Research Funding for Postdoc (kyfyjj202414).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eY.Y. and ZC.L. drafted the manuscript. ZZ.L. and XX.C. collected and analyzed the clinical data of AECD. JY.Y. and WH.Z. reviewed and interpreted the radiologic imaging. J.X., XX.C. and WH.Z. participated in the study concept and design, revised this article critically for important intellectual content, and final approval of the version to be published. All authors contributed to revising the article and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe thank the clinical staff of the Department of Pediatrics. We gratefully acknowledge the patients and their families.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding authors (by email).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHaroche J, Cohen-Aubart F, Amoura Z (2020) Erdheim-Chester disease. 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Neuro Oncol 23:1433\u0026ndash;1446. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1093/neuonc/noab107\u003c/span\u003e\u003cspan address=\"10.1093/neuonc/noab107\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pediatric, Erdheim-Chester disease, clinical features, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-8300528/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8300528/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003ePediatric-onset Erdheim-Chester disease (PECD) are more infrequently reported than adult population (AECD). This study aimed to explored the distinctive characteristics of PECD.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study compared the differences in clinical manifestations, laboratory/imaging characteristics, treatment responses, and outcomes between PECD and AECD from the same center and period.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 5 children with PECD and sixty-seven patients with AECD were ultimately included. Central nervous system and hypothalamic/pituitary involvement was frequently encountered in children (more than 50%). Pediatric-onset patients exhibited distinct patterns of organ involvement, with lower rates of bone involvement (60.0% vs. 97.0%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022) and cardiac/large vessel involvement (0% vs. 65.7%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), compared with the AECD cohort. Analysis of osseous manifestations revealed significantly lower appendicular skeletal involvement in children [1/3 (33.3%) vs. 64/65 (98.5%); \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004]. Osteosclerosis predominated in both children (2/3, 66.7%) and adults (52/62, 83.9%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.505), while approximately one-third exhibited osteolytic lesions in both groups. Comparative analysis revealed significantly lower levels of inflammatory markers (\u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.05) in the PECD group. Compared with the AECD cohort, patients with PECD showed a trend toward higher progression-free survival (80.0% vs. 35.0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.196) and overall survival (100% vs. 80.5%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.382) rates.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003ePECD and AECD exhibit distinct differences in clinical manifestations and inflammatory response intensity. Pediatric patients appear to have better survival outcomes compared with adult patients. The consensus recommendations established for AECD may not be fully applicable to the pediatric population.\u003c/p\u003e","manuscriptTitle":"Clinical Features and Prognosis of Pediatric-Onset Erdheim-Chester Disease Compared with an Adult-Onset Cohort from the Same Center","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-22 09:17:59","doi":"10.21203/rs.3.rs-8300528/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"03706a94-fa68-40d2-adf6-951d7ba02c24","owner":[],"postedDate":"December 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-04T14:09:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-22 09:17:59","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8300528","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8300528","identity":"rs-8300528","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}