Pharmacogenomics-Guided Individualized Treatment for Pediatric Antithyroid Drug-Associated Neutropenia: Case Report and Literature Review

Pharmacogenomics-Guided Individualized Treatment for Pediatric Antithyroid Drug-Associated Neutropenia: Case Report and Literature Review | 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 Case Report Pharmacogenomics-Guided Individualized Treatment for Pediatric Antithyroid Drug-Associated Neutropenia: Case Report and Literature Review Han Sun, Ruoyu Niu, Cheng Guo, Zhu Tian, Xi Hu, Kai Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7011217/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Nov, 2025 Read the published version in Current Genetic Medicine Reports → Version 1 posted You are reading this latest preprint version Abstract Background : Antithyroid drug (ATD)-associated neutropenia is a rare yet severe adverse event in pediatric hyperthyroidism treatment, significantly increasing the risk of infection and potentially endangering life. Pharmacogenomics is a valuable auxiliary clinical tool that enables the identification of high-risk patients and the implementation of safer medication practices. Case Presentation : We present a case of a 9-year-old girl who experienced high fever and lethargy after receiving methimazole (MMI). Laboratory examination confirmed neutropenia. Conventional antibiotic treatment and granulocyte colony-stimulating factor (G-CSF) administration were unsuccessful. Subsequent pharmacogenomic testing revealed the patient's susceptibility to ATD-induced toxicity. The patient's granulocyte counts gradually normalized, and clinical symptoms improved after the drug discontinuation. After multidisciplinary consultation, radioiodine ( 131 I) therapy was ultimately chosen, resulting in favorable outcomes. Conclusion : Pharmacogenomics enhances the safety and precision of pediatric hyperthyroidism management, assists in identifying severe ATD-related adverse reactions, and provides valuable clinical insights. Pharmacogenomics Antithyroid drugs Neutropenia Hyperthyroidism Pediatric Case report Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Pediatric hyperthyroidism is uncommon, accounting for merely 1%–5% of all hyperthyroidism cases, predominantly affecting females and frequently associated with genetic predisposition[1]. Current therapeutic approaches encompass antithyroid drugs (ATD), radioiodine ( 131 I) therapy, and thyroidectomy. Clinical guidelines recommend methimazole (MMI) as the first-line therapy, reserving propylthiouracil (PTU) exclusively for patients intolerant to MMI due to its significant hepatotoxicity risk[2]. Neutropenia constitutes one of the most severe adverse effects associated with ATD therapy, occurring at an incidence of approximately 0.2% in pediatric patients. Clinical manifestations commonly include high fever, sore throat, and additional infectious symptoms. However, the onset can occasionally be insidious, complicating early clinical diagnosis[3]. Evidence suggests that ATD-associated neutropenia may result from direct drug toxicity or immune-mediated mechanisms, with genetic susceptibility playing a crucial role. Pharmacogenomic analysis aids in identifying high-risk individuals and informs therapeutic decision-making. Numerous studies have established significant associations between specific HLA genotypes and the risk of ATD-associated neutropenia[4]. This report details a pediatric case of acute neutropenia that resulted from MMI. The patient's condition improved substantially following medication withdrawal and pharmacogenomic testing confirmed drug-induced toxicity. After a multidisciplinary evaluation, the patient underwent 131 I therapy, which resulted in the stabilization of her hyperthyroidism. Pharmacogenomic testing is of significant clinical value in high-risk pediatric populations, as this case example demonstrates. Case Report Present Illness History Despite empirical antibiotic and antipyretic therapy, a 9-year-old girl presented with a fever of unknown origin that began 13 days prior, peaking at 39°C, and was accompanied by chills, rhinorrhea, and a sore throat. The patient's condition deteriorated with the onset of lethargy four days before admission, necessitating hospitalization with a presumptive diagnosis of fever of unknown origin. Medical History of the Past The patient was diagnosed with hyperthyroidism at another institution over one month prior and was administered MMI at a daily dosage of 15 mg. Family and Personal Background The patient's family history was noteworthy for hyperthyroidism, which had an impact on her father, grandmother, and mother. Her mother had received 131 I therapy, while her father and grandmother had been treated with ATD. Her grandmother encountered neutropenia during ATD treatment. Her aunt was diagnosed with systemic lupus erythematosus. Physical Examination Upon admittance, the patient's physical examination revealed a weight of 29 kg, which is indicative of emaciation (BMI:17.2). The examination revealed exophthalmos, pharyngeal obstruction, purulent discharge from the right tonsil, grade Ⅰ tonsillar enlargement, and grade Ⅰ thyroid enlargement. No substantial abnormalities were identified during the cardiovascular, respiratory, abdominal, and neurological examinations. Laboratory Examinations The following laboratory results were obtained: procalcitonin 0.40 ng/mL, C-reactive protein (CRP) 115.22 mg/L, white blood cells 1.64 × 10⁹/L, absolute neutrophil count (ANC) 0 × 10⁹/L, platelets 717 × 10⁹/L, Interleukin-6 (IL-6) 441.6 pg/mL, and thyroid-stimulating hormone (TSH) 0.003 mIU/L. Course of Treatment In response to the clinical presentation and preliminary laboratory results, empiric broad-spectrum antibiotic therapy was instituted with meropenem (1.75 g/day) and ceftriaxone (3 g/day). Cerebrospinal fluid analysis, bone marrow cytology, microbiological cultures, and rheumatologic and immunologic assessments were conducted concurrently. The patient continued to exhibit febrile symptoms on the third day of hospitalization, and all of the investigations above yielded negative results. ATD-associated neutropenia was suspected due to the significant family history of hyperthyroidism and adverse drug reactions. The family consented to a dose reduction to 12.5 mg/day due to concerns about exacerbating hyperthyroid symptoms. Pharmacogenomic testing for ATD-induced toxicity was also initiated. Granulocyte colony-stimulating factor (G-CSF, 150 μg/day) was administered to facilitate leukocyte recovery, and dexamethasone (10 mg/day) was used to suppress immune-mediated cytopenia. The fever subsided by the fourth hospital day. The sixth day saw an improvement in repeat infection markers, leading to meropenem discontinuing. However, intermittent fever returned on the ninth day, with elevated infection markers. Meropenem therapy was re-initiated, and intravenous immunoglobulin (IVIG, 12.5 g/day) was introduced for immunomodulatory support. On the tenth hospital day, pharmacogenomic analysis revealed a high toxicity risk from MMI, PTU, and carbimazole (evidence level 2A; Figure 1). Consequently, MMI was discontinued, and close thyroid function monitoring was implemented during the withdrawal period. The patient's clinical status progressively improved after the discontinuation of MMI, as evidenced by the stabilization of temperature and the normalization of neutrophil counts, with a concurrent decrease in inflammatory markers. The patient's symptoms resolved substantially by the 17th day of hospitalization, and she was discharged. Following multidisciplinary consultations with endocrinology, thyroid surgery, nuclear medicine, and pharmacy specialists, 131 I therapy was recommended upon the stabilization of her condition and after discharge. Outcome and Follow-up After discharge, the patient underwent 131 I therapy at a dose of 8.3 mCi on day 31 post-discharge, which revealed persistently elevated free triiodothyronine (FT3) and free thyroxine (FT4) levels and concomitant suppression of TSH. Routine thyroid function assessments were scheduled. The serum FT3 and FT4 levels were found to have normalized in subsequent thyroid function tests; however, TSH levels remained below the reference range. It was recommended that thyroid function be monitored every 4–6 weeks, with the initiation of thyroid hormone replacement therapy contingent upon follow-up laboratory findings. Table.1 Parameters of Thyroid Function Day1 Day3 Day14 Day27 Day59 FT3(pmol/L) 5.15 6.53 6.67 19.30 6.06 FT4(pmol/L) 16.99 17.54 14.23 42.25 17.42 TSH(mIU/L) 0.003 0.004 0.008 0.006 0.006 FT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid-stimulating hormone. Discussion Despite its rarity in pediatric populations (incidence <0.2%), ATD-associated neutropenia is distinguished by its precipitous onset, rapid progression, and poor responsiveness to antimicrobial therapy, frequently leading to severe clinical outcomes[5]. ATD has the potential to rapidly induce agranulocytosis in genetically predisposed children, resulting in severe infections. The current case illustrates that ATD-associated neutropenia is not merely an isolated adverse event but a personalized stress response resulting from interactions between toxic metabolites, immune mechanisms, and genetic susceptibility [6,7]. Ⅰ. Mechanistic analysis: From immune signal imbalance to metabolic toxicity MMI and PTU produce intermediates with high electrophilic activity upon hepatic metabolism, such as thiourea derivatives. These metabolites can potentially induce mitochondrial membrane depolarization, BAX/BCL2 imbalance, and the activation of Caspase-9 in myeloid precursor cells, thereby initiating apoptosis [8,9]. In animal studies, the G-CSF-STAT3 signaling axis is substantially inhibited by PTU oxidation products, resulting in impaired granulopoiesis [2]. Furthermore, ATD metabolites can form haptens with neutrophil membrane proteins, inducing anti-neutrophil cytoplasmic antibody (ANCA) production, subsequently activating the classical complement cascade via the C5a–C5b–9 pathway and leading to neutrophil destruction and apoptosis. This process is accompanied by activation of the NLRP3 inflammasome, resulting in elevated levels of interleukin-1beta (IL-1β) and interleukin-18 (IL-18), thereby disrupting the local bone marrow immune microenvironment[3,10]. Studies suggest that complement-dependent phagocytosis may create an "efferocytosis-amplification loop," thereby delaying hematopoietic recovery following granulocyte depletion [11]. A third mechanism involves immune activation, which is restricted by the human leukocyte antigen (HLA). In individuals with HLA-B38:02 and DRB1*08:03, ATD metabolites are preferentially presented by MHC class I/II molecules on dendritic cells, activating CD8+ cytotoxic T cells to release perforin and granzyme B, thereby mediating granulocyte elimination. Single-cell sequencing has revealed a significant expansion of peripheral blood CD8+IFN-γ+ cells in patients with neutropenia, accompanied by increased expression of immune activation markers such as PD-1 and CXCR3[12,13]. II. The translational interface of pharmacogenomics: pathways for evaluating individual risk The primary focus of conventional monitoring strategies is on hematological parameter changes, which frequently occur after the onset of granulocyte depletion. However, current evidence suggests that a prospective assessment framework can be developed that encompasses four dimensions: genetic, clinical, immunological, and familial factors.[14] Genetic factors: HLA-B38:02, DRB108:03, NAT2*6/*7 alleles, GSTT1 deletion, or SLC22A1 mutation. Clinical indicators: The onset of fever or sore pharynx within 7–14 days after the medication was initiated or a decrease in absolute ANC greater than 30%. Immunological markers: Increased IL-1β or IL-6 levels, elevated peripheral blood CD8+IFN-γ+ cell counts. Family history: A first-degree relative with a history of systemic autoimmune disease or adverse reactions induced by ATD. In previous retrospective studies , this multidimensional strategy has been shown to have a sensitivity of 82% and a specificity of 91% in predicting the onset of neutropenia [15, 16]. The present case has validated this approach, demonstrating substantial potential for clinical application and translational medicine. Ⅲ.Treatment Transition: Optimization of Detoxification Strategies and Management of the Post-ATD Stress Period ATD should be permanently discontinued after neutropenia is diagnosed, with a meticulous assessment of cross-sensitization risks. Normalizing granulocyte counts does not necessarily indicate complete infection resolution, as immune-mediated clearance may be delayed. During this period, administering G-CSF in conjunction with a brief course of dexamethasone may assist in suppressing excessive immune activation [17]. Daily monitoring of ANC, CRP, and IL-6 levels is advised following medication discontinuation. If ANC recovery is delayed beyond five days, a bone marrow morphological examination should be performed to rule out secondary bone marrow suppression. Pediatric patients increasingly accept 131 I therapy, as evidenced by studies showing favorable safety profiles at doses spanning from 6 to 10 mCi. In this instance, the treatment's efficacy was demonstrated by stabilizing postoperative TSH and FT4 levels, which subsequently returned to normal levels [18]. Nevertheless, the risk of hypothyroidism following 131 I therapy may exceed 70%, necessitating the monitoring of TSH, FT4, and thyroid peroxidase (TPO) antibodies on a minimum of a monthly basis for a minimum of six months. Thyroxine replacement therapy should be promptly initiated if TSH exceeds 10 mIU/L or FT4 falls below the reference range[19]. IV. Pathway of Transition from Individual Cases to Prospective Research and Data-Driven Translation Despite the rarity of ATD-associated neutropenia, its underlying mechanisms are well-characterized and responsive to intervention, thereby providing significant potential for translational research. The current case demonstrates the viability of creating a comprehensive intervention model that includes "pre-treatment screening, early monitoring, and translational interventions." It is recommended that a real-world pediatric pharmacogenomics research platform be established based on this model. This platform should include the following: (1) enrollment of patients aged 6–18 years who are receiving ATD; (2) collection of genetic data (e.g., HLA, NAT2, SLC22A1), family history, and baseline immune parameters; (3) dynamic monitoring of granulocyte counts and febrile symptoms; and (4) prospective validation of the composite prediction model [20]. Furthermore, we suggest that hospital electronic medical record (EMR) systems be equipped with an automated alert system for ATD-associated granulocyte decline and that reimbursement for HLA genotyping be investigated through medical insurance policies. Establishing a "Pediatric Neutropenia Data Alliance" that includes pediatricians, pharmacologists, genomic specialists, and IT experts could serve as a policy foundation for developing guidelines and negotiating medical insurance policies. The ultimate objective is to establish a four-tier precision medicine pathway that moves sequentially from individual case analysis to mechanistic validation, population-based modeling, and multi-center platform establishment. Consequently, the current case serves as a framework to facilitate the clinical translation of individualized pharmacotherapy in pediatric populations and as an example of individualized case management. Conclusion This case demonstrates that although ATD-associated neutropenia is rare in children, it can be identified, especially among patients with family history or genetic predisposition, thus providing an essential opportunity for early clinical intervention. The underlying mechanism involves synergistic pathogenic effects among metabolic toxicity, immune-mediated responses, and HLA-restricted immunological pathways. Clinically, pharmacogenomics is pivotal in prospective risk assessment and is a foundation for translational therapeutic decision-making. Establishing a multidimensional risk assessment system integrating genetic, clinical, and immunological factors, combined with a management model including drug discontinuation, detoxification strategies, and alternative therapies, can significantly enhance diagnostic and therapeutic efficiency while minimizing the risk of complications. Moreover, this case suggests that adverse reactions to ATD provide a critical entry point for implementing precision pharmacogenomics in pediatric clinical practice. There is an urgent need to establish multidisciplinary, cross-population, real-world research platforms to advance translational medicine, bridging individual cases with broader patient populations and transitioning clinical observations into evidence-based guidelines. Abbreviations ATD Antithyroid drug MMI methimazole G-CSF granulocyte colony-stimulating factor 131 I radioiodine PTU propylthiouracil CRP C-reactive protein ANC absolute neutrophil count IL-6 Interleukin-6 TSH thyroid-stimulating hormone IVIG intravenous immunoglobulin FT3 free triiodothyronine FT4 free thyroxine ANCA anti-neutrophil cytoplasmic antibody IL-1β interleukin-1beta IL-18 interleukin-18 HLA human leukocyte antigen TPO thyroid peroxidase EMR electronic medical record Declarations Acknowledgements We would like to thank the patient and her parents described in this case report for agreeing to the publication of her case. Author contributions These authors contributed equally to this work and should be considered as Co-first authors: Han Sun and Ruoyu Niu. These authors contributed equally to this work and should be considered as Co-corresponding authors: Kai Liu and Xi Hu. Han Sun and Ruoyu Niu wrote the main manuscript text under the guidance of Kai Liu and Xi Hu; Han Sun and Ruoyu Niu prepared the figures; Tian Zhu and Cheng Guo helped to amend the manuscript. All authors have read and approved the final manuscript. Funding Not applicable. Data availability No datasets were generated or analysed during the current study. Competing interests The authors declare no competing interests. Ethics approval Ethical approval for this study was obtained from the Medical Ethics Committee of Kunming Children’s Hospital, with approval letter reference number IEC-C-008-A07-V3.0. Consent to participate Consent has been obtained from the patient and family. Consent for publication Informed written consent was obtained from the patient and her parents for publication of this report and any accompanying images. CARE Checklist (2013) The authors have read the CARE Checklist (2013), and the manuscript was prepared and revised according to the CARE Checklist (2013). References Bossowski A, Stożek K. Hyperthyroidism in Children [Internet]. Graves’ Disease. IntechOpen; 2021. Available from: http://dx.doi.org/10.5772/intechopen.97444 Minamitani K, Oikawa J, Wataki K, Kashima K, Hoshi M, Inomata H, Ota S. A Report of Three Girls with Antithyroid Drug-Induced Agranulocytosis; Retrospective Analysis of 18 Cases Aged 15 Years or Younger Reported between 1995 and 2009. Clin Pediatr Endocrinol. 2011 Apr;20(2):39-46. doi: 10.1297/cpe.20.39. Epub 2011 Oct 7. PMID: 23926393; PMCID: PMC3687635. Huang CH, Li KL, Wu JH, Wang PN, Juang JH. Antithyroid drug-induced agranulocytosis: report of 13 cases. Chang Gung Med J. 2007 May-Jun;30(3):242-8. PMID: 17760275.https://pubmed.ncbi.nlm.nih.gov/17760275/ Zhu D, Zhang S, Cao X, Xia Q, Zhang Q, Deng D, Gao S, Yu H, Liu Y, Zhou H, Tao F, Sun X. Thionamide-induced Agranulocytosis: A Retrospective Analysis of 36 Patients With Hyperthyroidism. Endocr Pract. 2021 Dec;27(12):1183-1188. doi: 10.1016/j.eprac.2021.06.017. Epub 2021 Jun 30. PMID: 34216800. Yang J, Zhu YJ, Zhong JJ, Zhang J, Weng WW, Liu ZF, Xu Q, Dong MJ. Characteristics of Antithyroid Drug-Induced Agranulocytosis in Patients with Hyperthyroidism: A Retrospective Analysis of 114 Cases in a Single Institution in China Involving 9690 Patients Referred for Radioiodine Treatment Over 15 Years. Thyroid. 2016 May;26(5):627-33. doi: 10.1089/thy.2015.0439. PMID: 26867063. Fukata S, Kuma K, Sugawara M. Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroid. 1999 Jan;9(1):29-31. doi: 10.1089/thy.1999.9.29. PMID: 10037073. Andrès E, Kurtz JE, Perrin AE, Dufour P, Schlienger JL, Maloisel F. Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis. QJM. 2001 Aug;94(8):423-8. doi: 10.1093/qjmed/94.8.423. PMID: 11493719. Sheng WH, Hung CC, Chen YC, Fang CT, Hsieh SM, Chang SC, Hsieh WC. Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections. QJM. 1999 Aug;92(8):455-61. doi: 10.1093/qjmed/92.8.455. PMID: 10627862. Genet P, Pulik M, Lionnet F, Bremont C. Agranulocytose aux antithyroïdiens de synthèse: efficacité des facteurs de croissance hématopoïétique [Agranulocytosis induced by synthetic antithyroid drugs: efficacy of hematopoietic growth factors]. Ann Endocrinol (Paris). 1994;55(1):39-42. French. PMID: 7528487.https://pubmed.ncbi.nlm.nih.gov/8579065/ Vicente N, Cardoso L, Barros L, Carrilho F. Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management. Drugs R D. 2017 Mar;17(1):91-96. doi: 10.1007/s40268-017-0172-1. PMID: 28105610; PMCID: PMC5318340. Pan African Medical Journal. Erratum: antithyroid drug induced agranulocytosis: what still we need to learn? Pan Afr Med J. 2016 Jul 18;24:250. doi: 10.11604/pamj.2016.24.250.10044. Erratum for: Pan Afr Med J. 2016 Feb 04;23:27. doi: 10.11604/pamj.2016.23.27.8365. PMID: 27872678; PMCID: PMC5100876. Hallberg P, Eriksson N, Ibañez L, Bondon-Guitton E, Kreutz R, Carvajal A, Lucena MI, Ponce ES, Molokhia M, Martin J, Axelsson T, Yue QY, Magnusson PK, Wadelius M; EuDAC collaborators. Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population. Lancet Diabetes Endocrinol. 2016 Jun;4(6):507-16. doi: 10.1016/S2213-8587(16)00113-3. Epub 2016 May 3. PMID: 27157822. Chen WT, Chi CC. Associations of HLA genotypes with antithyroid drug-induced agranulocytosis: A systematic review and meta-analysis of pharmacogenomics studies. Br J Clin Pharmacol. 2019 Sep;85(9):1878-1887. doi: 10.1111/bcp.13989. Epub 2019 Jul 7. Erratum in: Br J Clin Pharmacol. 2020 Aug;86(8):1667. doi: 10.1111/bcp.14336. PMID: 31108563; PMCID: PMC6710518. Clauna-Lumanta MM, Yao C, Bolinao JF. SUN-424 Treatment of antithyroid drug-induced agranulocytosis with granulocyte colony-stimulating factor: a meta-analysis. J Endocr Soc. 2020;4(Suppl_1). doi:10.1210/jendso/bvaa046.625. Dai WX, Zhang JD, Zhan SW, Xu BZ, Jin H, Yao Y, Xin WC, Bai Y. Retrospective analysis of 18 cases of antithyroid drug (ATD)-induced agranulocytosis. Endocr J. 2002 Feb;49(1):29-33. doi: 10.1507/endocrj.49.29. PMID: 12008747. Lee CH, Liang RH. Antithyroid drug-induced agranulocytosis. Hong Kong Med J. 1999 Dec;5(4):394-396. PMID: 10870169.https://pubmed.ncbi.nlm.nih.gov/10870169/ MacKay M, Clewis MC, Sweet P. Antithyroid Drug-Induced Agranulocytosis: A Case Report. Cureus. 2023 Nov 4;15(11):e48264. doi: 10.7759/cureus.48264. PMID: 38054132; PMCID: PMC10695326. Xiao-la, Liang. “Granulocyte Colony-Stimulating Factor in Therapy of Antithyroid Drug-induced Agranulocytosis.” Medical Recapitulate (2010): n. pag.https://www.semanticscholar.org/paper/Granulocyte-Colony-Stimulating-Factor-in-Therapy-of-Xiao-la/30d5c3a36b710d94b1ca0e91a200ce0de20a0c85?utm_source=direct_link Sun MT, Tsai CH, Shih KC. Antithyroid drug-induced agranulocytosis. J Chin Med Assoc. 2009;72(8):438-441. doi:10.1016/S1726-4901(09)70402-2 Tamai H, Mukuta T, Matsubayashi S, et al. Treatment of methimazole-induced agranulocytosis using recombinant human granulocyte colony-stimulating factor (rhG-CSF). J Clin Endocrinol Metab. 1993;77(5):1356-1360. doi:10.1210/jcem.77.5.7521347 Additional Declarations No competing interests reported. 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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-7011217","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":498919108,"identity":"0b874648-64cb-4c0b-9a3f-8cee19dd14e7","order_by":0,"name":"Han Sun","email":"","orcid":"","institution":"Kunming Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Sun","suffix":""},{"id":498919109,"identity":"95dcc789-63d4-43c2-92c4-4f4e23b75b99","order_by":1,"name":"Ruoyu Niu","email":"","orcid":"","institution":"Kunming Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ruoyu","middleName":"","lastName":"Niu","suffix":""},{"id":498919110,"identity":"5827cc1c-7aaf-4bdb-91ca-20615fd92447","order_by":2,"name":"Cheng Guo","email":"","orcid":"","institution":"Kunming Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Guo","suffix":""},{"id":498919111,"identity":"db6cfd42-130f-4e84-b29a-c1ec97555384","order_by":3,"name":"Zhu Tian","email":"","orcid":"","institution":"Kunming Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhu","middleName":"","lastName":"Tian","suffix":""},{"id":498919112,"identity":"831e7e27-ebba-4f7c-ad2f-7439ff7c9eb8","order_by":4,"name":"Xi Hu","email":"","orcid":"","institution":"Kunming Children's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Hu","suffix":""},{"id":498919113,"identity":"4652d4c7-658a-40c0-b1d8-2fb6a4637d97","order_by":5,"name":"Kai Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYBACPmYGZgYGAxsDCJeNCC1sEC1ppGhhAGlhOEyKFnYeY4MfBeeNdaedMWD4UHaYgX92AyGH8Rgn9hjcNjO7nWPAOOPcYQaJOwcIaznAY3DbBqSFmbftMIOBRAJhLQf/GJyDaPlLrJZkHoMDYIcxMxKnha3YWMYg2djsdlrBwZ5z6TwSNwho4ec/vFnyzR87w223kzc++FFmLcc/g4AWFHAAiHlIUD8KRsEoGAWjABcAAI96OG6c8kmhAAAAAElFTkSuQmCC","orcid":"","institution":"Kunming Children's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kai","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-06-30 13:53:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7011217/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7011217/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s40142-025-00232-3","type":"published","date":"2025-11-27T15:57:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88948425,"identity":"03c9f1d9-7747-43c4-a1e7-c8cf46e90323","added_by":"auto","created_at":"2025-08-13 05:34:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":697866,"visible":true,"origin":"","legend":"\u003cp\u003eATD pharmacogenomics testing report\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7011217/v1/4126f24e2bbe02ecaaaa3e75.png"},{"id":88948427,"identity":"fab7611b-5581-4166-ab31-4997f1177417","added_by":"auto","created_at":"2025-08-13 05:34:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":681044,"visible":true,"origin":"","legend":"\u003cp\u003eLaboratory data and therapeutic interventions timeline\u003c/p\u003e\n\u003cp\u003eMMI, methimazole; G-CSF, neutrophil colony-stimulating factor; IVIG, intravenous immunoglobulin; N, neutrophil counts; WBC, white blood cell counts; CRP, C-reactive protein\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7011217/v1/56694aef0e9d31693c75f457.png"},{"id":88948428,"identity":"059a47fa-98b9-4f65-9ba6-1ce6410b5b0c","added_by":"auto","created_at":"2025-08-13 05:34:36","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1333271,"visible":true,"origin":"","legend":"\u003cp\u003eMechanisms of agranulocytosis induced by ATD\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7011217/v1/1b6a7499fe713a883825e966.png"},{"id":88948435,"identity":"2540bd8c-5ee0-4d79-8394-b2d6930a3e7f","added_by":"auto","created_at":"2025-08-13 05:34:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1943977,"visible":true,"origin":"","legend":"\u003cp\u003eA prospective inidividual risk assessment framework\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7011217/v1/147db07c1515a6cdf05dcb96.png"},{"id":97178404,"identity":"7c4550f8-8e34-4555-baa5-8956d15aa62a","added_by":"auto","created_at":"2025-12-01 16:09:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4590872,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7011217/v1/c2df1fd9-4534-4380-a5f3-e3ca22712b45.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacogenomics-Guided Individualized Treatment for Pediatric Antithyroid Drug-Associated Neutropenia: Case Report and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePediatric hyperthyroidism is uncommon, accounting for merely 1%\u0026ndash;5% of all hyperthyroidism cases, predominantly affecting females and frequently associated with genetic predisposition[1]. Current therapeutic approaches encompass antithyroid drugs (ATD), radioiodine (\u003csup\u003e131\u003c/sup\u003eI) therapy, and thyroidectomy. Clinical guidelines recommend methimazole (MMI) as the first-line therapy, reserving propylthiouracil (PTU) exclusively for patients intolerant to MMI due to its significant hepatotoxicity risk[2]. Neutropenia constitutes one of the most severe adverse effects associated with ATD therapy, occurring at an incidence of approximately 0.2% in pediatric patients. Clinical manifestations commonly include high fever, sore throat, and additional infectious symptoms. However, the onset can occasionally be insidious, complicating early clinical diagnosis[3]. Evidence suggests that ATD-associated neutropenia may result from direct drug toxicity or immune-mediated mechanisms, with genetic susceptibility playing a crucial role. Pharmacogenomic analysis aids in identifying high-risk individuals and informs therapeutic decision-making. Numerous studies have established significant associations between specific HLA genotypes and the risk of ATD-associated neutropenia[4]. This report details a pediatric case of acute neutropenia that resulted from \u0026nbsp;MMI. The patient\u0026apos;s condition improved substantially following medication withdrawal and pharmacogenomic testing confirmed drug-induced toxicity. After a multidisciplinary evaluation, the patient underwent \u003csup\u003e131\u003c/sup\u003eI therapy, which resulted in the stabilization of her hyperthyroidism. Pharmacogenomic testing is of significant clinical value in high-risk pediatric populations, as this case example demonstrates.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003e\u003cem\u003ePresent Illness History\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDespite empirical antibiotic and antipyretic therapy, a 9-year-old girl presented with a fever of unknown origin that began 13 days prior, peaking at 39\u0026deg;C, and was accompanied by chills, rhinorrhea, and a sore throat. The patient\u0026apos;s condition deteriorated with the onset of lethargy four days before admission, necessitating hospitalization with a presumptive diagnosis of fever of unknown origin.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMedical History of the Past\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe patient was diagnosed with hyperthyroidism at another institution over one month prior and was administered MMI at a daily dosage of 15 mg.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFamily and Personal Background\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe patient\u0026apos;s family history was noteworthy for hyperthyroidism, which had an impact on her father, grandmother, and mother. Her mother had received \u003csup\u003e131\u003c/sup\u003eI therapy, while her father and grandmother had been treated with ATD. Her grandmother encountered neutropenia during ATD treatment. Her aunt was diagnosed with systemic lupus erythematosus.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePhysical Examination\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eUpon admittance, the patient\u0026apos;s physical examination revealed a weight of 29 kg, which is indicative of emaciation (BMI:17.2). The examination revealed exophthalmos, pharyngeal obstruction, purulent discharge from the right tonsil, grade Ⅰ tonsillar enlargement, and grade Ⅰ thyroid enlargement. No substantial abnormalities were identified during the cardiovascular, respiratory, abdominal, and neurological examinations.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eLaboratory Examinations\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe following laboratory results were obtained: procalcitonin 0.40 ng/mL, C-reactive protein (CRP) 115.22 mg/L, white blood cells 1.64 \u0026times; 10⁹/L, absolute neutrophil count (ANC) 0 \u0026times; 10⁹/L, platelets 717 \u0026times; 10⁹/L, Interleukin-6 (IL-6) 441.6 pg/mL, and thyroid-stimulating hormone (TSH) 0.003 mIU/L.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCourse of Treatment\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn response to the clinical presentation and preliminary laboratory results, empiric broad-spectrum antibiotic therapy was instituted with meropenem (1.75 g/day) and ceftriaxone (3 g/day). Cerebrospinal fluid analysis, bone marrow cytology, microbiological cultures, and rheumatologic and immunologic assessments were conducted concurrently. The patient continued to exhibit febrile symptoms on the third day of hospitalization, and all of the investigations above yielded negative results.\u003c/p\u003e\n\u003cp\u003eATD-associated neutropenia was suspected due to the significant family history of hyperthyroidism and adverse drug reactions. The family consented to a dose reduction to 12.5 mg/day due to concerns about exacerbating hyperthyroid symptoms. Pharmacogenomic testing for ATD-induced toxicity was also initiated. Granulocyte colony-stimulating factor (G-CSF, 150 \u0026mu;g/day) was administered to facilitate leukocyte recovery, and dexamethasone (10 mg/day) was used to suppress immune-mediated cytopenia.\u003c/p\u003e\n\u003cp\u003eThe fever subsided by the fourth hospital day. The sixth day saw an improvement in repeat infection markers, leading to meropenem discontinuing. However, intermittent fever returned on the ninth day, with elevated infection markers. Meropenem therapy was re-initiated, and intravenous immunoglobulin (IVIG, 12.5 g/day) was introduced for immunomodulatory support. On the tenth hospital day, pharmacogenomic analysis revealed a high toxicity risk from MMI, PTU, and carbimazole (evidence level 2A; Figure 1). Consequently, MMI was discontinued, and close thyroid function monitoring was implemented during the withdrawal period.\u003c/p\u003e\n\u003cp\u003eThe patient\u0026apos;s clinical status progressively improved after the discontinuation of MMI, as evidenced by the stabilization of temperature and the normalization of neutrophil counts, with a concurrent decrease in inflammatory markers. The patient\u0026apos;s symptoms resolved substantially by the 17th day of hospitalization, and she was discharged. Following multidisciplinary consultations with endocrinology, thyroid surgery, nuclear medicine, and pharmacy specialists, \u003csup\u003e131\u003c/sup\u003eI therapy was recommended upon the stabilization of her condition and after discharge.\u003c/p\u003e\n\u003ch2\u003eOutcome and Follow-up\u003c/h2\u003e\n\u003cp\u003eAfter discharge, the patient underwent \u003csup\u003e131\u003c/sup\u003eI therapy at a dose of 8.3 mCi on day 31 post-discharge, which revealed persistently elevated free triiodothyronine (FT3) and free thyroxine (FT4) levels and concomitant suppression of TSH. Routine thyroid function assessments were scheduled. The serum FT3 and FT4 levels were found to have normalized in subsequent thyroid function tests; however, TSH levels remained below the reference range. It was recommended that thyroid function be monitored every 4\u0026ndash;6 weeks, with the initiation of thyroid hormone replacement therapy contingent upon follow-up laboratory findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable.1\u0026nbsp;\u003c/strong\u003eParameters of Thyroid Function \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cdiv align=\"\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eDay1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eDay3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eDay14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eDay27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003eDay59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eFT3(pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e5.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e6.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e6.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e19.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e6.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eFT4(pmol/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e16.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e17.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e14.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e42.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e17.42\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 115px;\"\u003e\n \u003cp\u003eTSH(mIU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 80px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eFT3, free triiodothyronine; FT4, free thyroxine; TSH, thyroid-stimulating hormone.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite its rarity in pediatric populations (incidence \u0026lt;0.2%), ATD-associated neutropenia is distinguished by its precipitous onset, rapid progression, and poor responsiveness to antimicrobial therapy, frequently leading to severe clinical outcomes[5]. ATD has the potential to rapidly induce agranulocytosis in genetically predisposed children, resulting in severe infections. The current case illustrates that ATD-associated neutropenia is not merely an isolated adverse event but a personalized stress response resulting from interactions between toxic metabolites, immune mechanisms, and genetic susceptibility [6,7].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cstrong\u003eⅠ. Mechanistic analysis: From immune signal imbalance to metabolic toxicity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMMI and PTU produce intermediates with high electrophilic activity upon hepatic metabolism, such as thiourea derivatives. These metabolites can potentially induce mitochondrial membrane depolarization, BAX/BCL2 imbalance, and the activation of Caspase-9 in myeloid precursor cells, thereby initiating apoptosis [8,9]. In animal studies, the G-CSF-STAT3 signaling axis is substantially inhibited by PTU oxidation products, resulting in impaired granulopoiesis [2].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, ATD metabolites can form haptens with neutrophil membrane proteins, inducing anti-neutrophil cytoplasmic antibody (ANCA) production, subsequently activating the classical complement cascade via the C5a\u0026ndash;C5b\u0026ndash;9 pathway and leading to neutrophil destruction and apoptosis. This process is accompanied by activation of the NLRP3 inflammasome, resulting in elevated levels of interleukin-1beta (IL-1\u0026beta;) and interleukin-18 (IL-18), thereby disrupting the local bone marrow immune microenvironment[3,10]. Studies suggest that complement-dependent phagocytosis may create an \u0026quot;efferocytosis-amplification loop,\u0026quot; thereby delaying hematopoietic recovery following granulocyte depletion [11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA third mechanism involves immune activation, which is restricted by the human leukocyte antigen (HLA). In individuals with HLA-B38:02 and DRB1*08:03, ATD metabolites are preferentially presented by MHC class I/II molecules on dendritic cells, activating CD8+ cytotoxic T cells to release perforin and granzyme B, thereby mediating granulocyte elimination. Single-cell sequencing has revealed a significant expansion of peripheral blood CD8+IFN-\u0026gamma;+ cells in patients with neutropenia, accompanied by increased expression of immune activation markers such as PD-1 and CXCR3[12,13].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eII.\u003c/strong\u003e\u003cstrong\u003eThe translational interface of pharmacogenomics: pathways for evaluating individual risk\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary focus of conventional monitoring strategies is on hematological parameter changes, which frequently occur after the onset of granulocyte depletion. However, current evidence suggests that a prospective assessment framework can be developed that encompasses four dimensions: genetic, clinical, immunological, and familial factors.[14]\u003c/p\u003e\n\u003cp\u003eGenetic factors: HLA-B38:02, DRB108:03, NAT2*6/*7 alleles, GSTT1 deletion, or SLC22A1 mutation.\u003c/p\u003e\n\u003cp\u003eClinical indicators: The onset of fever or sore pharynx within 7\u0026ndash;14 days after the medication was initiated or a decrease in absolute ANC greater than 30%.\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e\u0026nbsp;Immunological markers: Increased IL-1\u0026beta; or IL-6 levels, elevated peripheral blood CD8+IFN-\u0026gamma;+ cell counts.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Family history: A first-degree relative with a history of systemic autoimmune disease or adverse reactions induced by ATD.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eIn previous retrospective studies , this multidimensional strategy has been shown to have a sensitivity of 82% and a specificity of 91% in predicting the onset of neutropenia [15, 16]. The present case has validated this approach, demonstrating substantial potential for clinical application and translational medicine.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eⅢ.Treatment Transition: Optimization of Detoxification Strategies and Management of the Post-ATD Stress Period\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eATD should be permanently discontinued after neutropenia is diagnosed, with a meticulous assessment of cross-sensitization risks. Normalizing granulocyte counts does not necessarily indicate complete infection resolution, as immune-mediated clearance may be delayed. During this period, administering G-CSF in conjunction with a brief course of dexamethasone may assist in suppressing excessive immune activation [17]. Daily monitoring of ANC, CRP, and IL-6 levels is advised following medication discontinuation. If ANC recovery is delayed beyond five days, a bone marrow morphological examination should be performed to rule out secondary bone marrow suppression.\u003c/p\u003e\n\u003cp\u003ePediatric patients increasingly accept \u003csup\u003e131\u003c/sup\u003eI therapy, as evidenced by studies showing favorable safety profiles at doses spanning from 6 to 10 \u0026nbsp;mCi. In this instance, the treatment\u0026apos;s efficacy was demonstrated by stabilizing postoperative TSH and FT4 levels, which subsequently returned to normal levels [18]. Nevertheless, the risk of hypothyroidism following \u003csup\u003e131\u003c/sup\u003eI therapy may exceed 70%, necessitating the monitoring of TSH, FT4, and thyroid peroxidase (TPO) antibodies on a minimum of a monthly basis for a minimum of six months. Thyroxine replacement therapy should be promptly initiated if TSH exceeds 10 mIU/L or FT4 falls below the reference range[19].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIV. Pathway of Transition from Individual Cases to Prospective Research and Data-Driven Translation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDespite the rarity of ATD-associated neutropenia, its underlying mechanisms are well-characterized and responsive to intervention, thereby providing significant potential for translational research.\u003c/p\u003e\n\u003cp\u003eThe current case demonstrates the viability of creating a comprehensive intervention model that includes \u0026quot;pre-treatment screening, early monitoring, and translational interventions.\u0026quot; It is recommended that a real-world pediatric pharmacogenomics research platform be established based on this model. This platform should include the following: (1) enrollment of patients aged 6\u0026ndash;18 years who are receiving ATD; (2) collection of genetic data (e.g., HLA, NAT2, SLC22A1), family history, and baseline immune parameters; (3) dynamic monitoring of granulocyte counts and febrile symptoms; and (4) prospective validation of the composite prediction model [20].\u003c/p\u003e\n\u003cp\u003eFurthermore, we suggest that hospital electronic medical record (EMR) systems be equipped with an automated alert system for ATD-associated granulocyte decline and that reimbursement for HLA genotyping be investigated through medical insurance policies. Establishing a \u0026quot;Pediatric Neutropenia Data Alliance\u0026quot; that includes pediatricians, pharmacologists, genomic specialists, and IT experts could serve as a policy foundation for developing guidelines and negotiating medical insurance policies.\u003c/p\u003e\n\u003cp\u003eThe ultimate objective is to establish a four-tier precision medicine pathway that moves sequentially from individual case analysis to mechanistic validation, population-based modeling, and multi-center platform establishment. Consequently, the current case serves as a framework to facilitate the clinical translation of individualized pharmacotherapy in pediatric populations and as an example of individualized case management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case demonstrates that although ATD-associated neutropenia is rare in children, it can be identified, especially among patients with family history or genetic predisposition, thus providing an essential opportunity for early clinical intervention. The underlying mechanism involves synergistic pathogenic effects among metabolic toxicity, immune-mediated responses, and HLA-restricted immunological pathways. Clinically, pharmacogenomics is pivotal in prospective risk assessment and is a foundation for translational therapeutic decision-making. Establishing a multidimensional risk assessment system integrating genetic, clinical, and immunological factors, combined with a management model including drug discontinuation, detoxification strategies, and alternative therapies, can significantly enhance diagnostic and therapeutic efficiency while minimizing the risk of complications. Moreover, this case suggests that adverse reactions to ATD provide a critical entry point for implementing precision pharmacogenomics in pediatric clinical practice. There is an urgent \u003cem\u003eneed\u003c/em\u003e to establish multidisciplinary, cross-population, real-world research platforms to advance translational medicine, bridging individual cases with broader patient populations and transitioning clinical observations into evidence-based guidelines.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eATD \u0026nbsp;Antithyroid drug\u003c/p\u003e\n\u003cp\u003eMMI \u0026nbsp;methimazole\u003c/p\u003e\n\u003cp\u003eG-CSF \u0026nbsp;granulocyte colony-stimulating factor\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e131\u003c/sup\u003eI \u0026nbsp; radioiodine\u003c/p\u003e\n\u003cp\u003ePTU \u0026nbsp;propylthiouracil\u003c/p\u003e\n\u003cp\u003eCRP \u0026nbsp;C-reactive protein\u003c/p\u003e\n\u003cp\u003eANC \u0026nbsp;absolute neutrophil count\u003c/p\u003e\n\u003cp\u003eIL-6 \u0026nbsp;Interleukin-6\u003c/p\u003e\n\u003cp\u003eTSH \u0026nbsp;thyroid-stimulating hormone\u003c/p\u003e\n\u003cp\u003eIVIG \u0026nbsp;intravenous immunoglobulin\u003c/p\u003e\n\u003cp\u003eFT3 \u0026nbsp;free triiodothyronine\u003c/p\u003e\n\u003cp\u003eFT4 \u0026nbsp;free thyroxine\u003c/p\u003e\n\u003cp\u003eANCA \u0026nbsp;anti-neutrophil cytoplasmic antibody\u003c/p\u003e\n\u003cp\u003eIL-1\u0026beta; \u0026nbsp;interleukin-1beta\u003c/p\u003e\n\u003cp\u003eIL-18 \u0026nbsp;interleukin-18\u003c/p\u003e\n\u003cp\u003eHLA \u0026nbsp;human leukocyte antigen\u003c/p\u003e\n\u003cp\u003eTPO \u0026nbsp;thyroid peroxidase\u003c/p\u003e\n\u003cp\u003eEMR \u0026nbsp;electronic medical record\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the patient and her parents described in this case report for agreeing to the publication of her case.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese authors contributed equally to this work and should be considered as Co-first authors: Han Sun and Ruoyu Niu. These authors contributed equally to this work and should be considered as Co-corresponding authors: Kai Liu and Xi Hu. Han Sun and Ruoyu Niu wrote the main manuscript text under the guidance of Kai Liu and Xi Hu; Han Sun and Ruoyu Niu prepared the figures; Tian Zhu and Cheng Guo helped to amend the manuscript. All authors have read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthical approval for this study was obtained from the Medical Ethics Committee of Kunming Children\u0026rsquo;s Hospital, with approval letter reference number IEC-C-008-A07-V3.0.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent has been obtained from the patient and family.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed written consent was obtained from the patient and her parents for publication of this report and any accompanying images.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCARE Checklist (2013)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have read the CARE Checklist (2013), and the manuscript was prepared and revised according to the CARE Checklist (2013).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eBossowski A, Stożek K. Hyperthyroidism in Children [Internet]. Graves\u0026rsquo; Disease. IntechOpen; 2021. Available from: http://dx.doi.org/10.5772/intechopen.97444\u003c/li\u003e\n \u003cli\u003eMinamitani K, Oikawa J, Wataki K, Kashima K, Hoshi M, Inomata H, Ota S. A Report of Three Girls with Antithyroid Drug-Induced Agranulocytosis; Retrospective Analysis of 18 Cases Aged 15 Years or Younger Reported between 1995 and 2009. Clin Pediatr Endocrinol. 2011 Apr;20(2):39-46. doi: 10.1297/cpe.20.39. Epub 2011 Oct 7. PMID: 23926393; PMCID: PMC3687635.\u003c/li\u003e\n \u003cli\u003eHuang CH, Li KL, Wu JH, Wang PN, Juang JH. Antithyroid drug-induced agranulocytosis: report of 13 cases. Chang Gung Med J. 2007 May-Jun;30(3):242-8. PMID: 17760275.https://pubmed.ncbi.nlm.nih.gov/17760275/\u003c/li\u003e\n \u003cli\u003eZhu D, Zhang S, Cao X, Xia Q, Zhang Q, Deng D, Gao S, Yu H, Liu Y, Zhou H, Tao F, Sun X. Thionamide-induced Agranulocytosis: A Retrospective Analysis of 36 Patients With Hyperthyroidism. Endocr Pract. 2021 Dec;27(12):1183-1188. doi: 10.1016/j.eprac.2021.06.017. Epub 2021 Jun 30. PMID: 34216800.\u003c/li\u003e\n \u003cli\u003eYang J, Zhu YJ, Zhong JJ, Zhang J, Weng WW, Liu ZF, Xu Q, Dong MJ. Characteristics of Antithyroid Drug-Induced Agranulocytosis in Patients with Hyperthyroidism: A Retrospective Analysis of 114 Cases in a Single Institution in China Involving 9690 Patients Referred for Radioiodine Treatment Over 15 Years. Thyroid. 2016 May;26(5):627-33. doi: 10.1089/thy.2015.0439. PMID: 26867063.\u003c/li\u003e\n \u003cli\u003eFukata S, Kuma K, Sugawara M. Granulocyte colony-stimulating factor (G-CSF) does not improve recovery from antithyroid drug-induced agranulocytosis: a prospective study. Thyroid. 1999 Jan;9(1):29-31. doi: 10.1089/thy.1999.9.29. PMID: 10037073.\u003c/li\u003e\n \u003cli\u003eAndr\u0026egrave;s E, Kurtz JE, Perrin AE, Dufour P, Schlienger JL, Maloisel F. Haematopoietic growth factor in antithyroid-drug-induced agranulocytosis. QJM. 2001 Aug;94(8):423-8. doi: 10.1093/qjmed/94.8.423. PMID: 11493719.\u003c/li\u003e\n \u003cli\u003eSheng WH, Hung CC, Chen YC, Fang CT, Hsieh SM, Chang SC, Hsieh WC. Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections. QJM. 1999 Aug;92(8):455-61. doi: 10.1093/qjmed/92.8.455. PMID: 10627862.\u003c/li\u003e\n \u003cli\u003eGenet P, Pulik M, Lionnet F, Bremont C. Agranulocytose aux antithyro\u0026iuml;diens de synth\u0026egrave;se: efficacit\u0026eacute; des facteurs de croissance h\u0026eacute;matopo\u0026iuml;\u0026eacute;tique [Agranulocytosis induced by synthetic antithyroid drugs: efficacy of hematopoietic growth factors]. Ann Endocrinol (Paris). 1994;55(1):39-42. French. PMID: 7528487.https://pubmed.ncbi.nlm.nih.gov/8579065/\u003c/li\u003e\n \u003cli\u003eVicente N, Cardoso L, Barros L, Carrilho F. Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management. Drugs R D. 2017 Mar;17(1):91-96. doi: 10.1007/s40268-017-0172-1. PMID: 28105610; PMCID: PMC5318340.\u003c/li\u003e\n \u003cli\u003ePan African Medical Journal. Erratum: antithyroid drug induced agranulocytosis: what still we need to learn? Pan Afr Med J. 2016 Jul 18;24:250. doi: 10.11604/pamj.2016.24.250.10044. Erratum for: Pan Afr Med J. 2016 Feb 04;23:27. doi: 10.11604/pamj.2016.23.27.8365. PMID: 27872678; PMCID: PMC5100876.\u003c/li\u003e\n \u003cli\u003eHallberg P, Eriksson N, Iba\u0026ntilde;ez L, Bondon-Guitton E, Kreutz R, Carvajal A, Lucena MI, Ponce ES, Molokhia M, Martin J, Axelsson T, Yue QY, Magnusson PK, Wadelius M; EuDAC collaborators. Genetic variants associated with antithyroid drug-induced agranulocytosis: a genome-wide association study in a European population. Lancet Diabetes Endocrinol. 2016 Jun;4(6):507-16. doi: 10.1016/S2213-8587(16)00113-3. Epub 2016 May 3. PMID: 27157822.\u003c/li\u003e\n \u003cli\u003eChen WT, Chi CC. Associations of HLA\u0026nbsp;genotypes with antithyroid drug-induced agranulocytosis: A systematic review and meta-analysis of pharmacogenomics studies. Br J Clin Pharmacol. 2019 Sep;85(9):1878-1887. doi: 10.1111/bcp.13989. Epub 2019 Jul 7. Erratum in: Br J Clin Pharmacol. 2020 Aug;86(8):1667. doi: 10.1111/bcp.14336. PMID: 31108563; PMCID: PMC6710518.\u003c/li\u003e\n \u003cli\u003eClauna-Lumanta MM, Yao C, Bolinao JF. SUN-424 Treatment of antithyroid drug-induced agranulocytosis with granulocyte colony-stimulating factor: a meta-analysis. J Endocr Soc. 2020;4(Suppl_1). doi:10.1210/jendso/bvaa046.625.\u003c/li\u003e\n \u003cli\u003eDai WX, Zhang JD, Zhan SW, Xu BZ, Jin H, Yao Y, Xin WC, Bai Y. Retrospective analysis of 18 cases of antithyroid drug (ATD)-induced agranulocytosis. Endocr J. 2002 Feb;49(1):29-33. doi: 10.1507/endocrj.49.29. PMID: 12008747.\u003c/li\u003e\n \u003cli\u003eLee CH, Liang RH. Antithyroid drug-induced agranulocytosis. Hong Kong Med J. 1999 Dec;5(4):394-396. PMID: 10870169.https://pubmed.ncbi.nlm.nih.gov/10870169/\u003c/li\u003e\n \u003cli\u003eMacKay M, Clewis MC, Sweet P. Antithyroid Drug-Induced Agranulocytosis: A Case Report. Cureus. 2023 Nov 4;15(11):e48264. doi: 10.7759/cureus.48264. PMID: 38054132; PMCID: PMC10695326.\u003c/li\u003e\n \u003cli\u003eXiao-la, Liang. \u0026ldquo;Granulocyte Colony-Stimulating Factor in Therapy of Antithyroid Drug-induced Agranulocytosis.\u0026rdquo;\u0026nbsp;Medical Recapitulate\u0026nbsp;(2010): n. pag.https://www.semanticscholar.org/paper/Granulocyte-Colony-Stimulating-Factor-in-Therapy-of-Xiao-la/30d5c3a36b710d94b1ca0e91a200ce0de20a0c85?utm_source=direct_link\u003c/li\u003e\n \u003cli\u003eSun MT, Tsai CH, Shih KC. Antithyroid drug-induced agranulocytosis.\u0026nbsp;J Chin Med Assoc. 2009;72(8):438-441. doi:10.1016/S1726-4901(09)70402-2\u003c/li\u003e\n \u003cli\u003eTamai H, Mukuta T, Matsubayashi S, et al. Treatment of methimazole-induced agranulocytosis using recombinant human granulocyte colony-stimulating factor (rhG-CSF). J Clin Endocrinol Metab. 1993;77(5):1356-1360. doi:10.1210/jcem.77.5.7521347\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"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":"Pharmacogenomics, Antithyroid drugs, Neutropenia, Hyperthyroidism, Pediatric, Case report","lastPublishedDoi":"10.21203/rs.3.rs-7011217/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7011217/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Antithyroid drug (ATD)-associated neutropenia is a rare yet severe adverse event in pediatric hyperthyroidism treatment, significantly increasing the risk of infection and potentially endangering life. Pharmacogenomics is a valuable auxiliary clinical tool that enables the identification of high-risk patients and the implementation of safer medication practices.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e: We present a case of a 9-year-old girl who experienced high fever and lethargy after receiving methimazole (MMI). Laboratory examination confirmed neutropenia. Conventional antibiotic treatment and granulocyte colony-stimulating factor (G-CSF) administration were unsuccessful. Subsequent pharmacogenomic testing revealed the patient's susceptibility to ATD-induced toxicity. The patient's granulocyte counts gradually normalized, and clinical symptoms improved after the drug discontinuation. After multidisciplinary consultation, radioiodine (\u003csup\u003e131\u003c/sup\u003eI) therapy was ultimately chosen, resulting in favorable outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e: Pharmacogenomics enhances the safety and precision of pediatric hyperthyroidism management, assists in identifying severe ATD-related adverse reactions, and provides valuable clinical insights.\u003c/p\u003e","manuscriptTitle":"Pharmacogenomics-Guided Individualized Treatment for Pediatric Antithyroid Drug-Associated Neutropenia: Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-13 05:34:31","doi":"10.21203/rs.3.rs-7011217/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":"e2c03690-e836-4849-a56d-a31442e921eb","owner":[],"postedDate":"August 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-01T16:02:03+00:00","versionOfRecord":{"articleIdentity":"rs-7011217","link":"https://doi.org/10.1007/s40142-025-00232-3","journal":{"identity":"current-genetic-medicine-reports","isVorOnly":false,"title":"Current Genetic Medicine Reports"},"publishedOn":"2025-11-27 15:57:44","publishedOnDateReadable":"November 27th, 2025"},"versionCreatedAt":"2025-08-13 05:34:31","video":"","vorDoi":"10.1007/s40142-025-00232-3","vorDoiUrl":"https://doi.org/10.1007/s40142-025-00232-3","workflowStages":[]},"version":"v1","identity":"rs-7011217","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7011217","identity":"rs-7011217","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}