This case presents the first reported CSF1R-related leukoencephalopathy with a non-hotspot c.2443-1G>C mutation complicated by invasive fungal infection after allo-HSCT. Microglial dysfunction in CSF1R-related disorder may amplify infection risk by impairing systemic immune surveillance post-transplant. A multidisciplinary team implemented a precision antifungal strategy integrating pharmacokinetics, immunologic status, and next-generation sequencing (tNGS) for pathogen identification.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare, autosomal dominant leukodystrophy characterized by severe disability and high mortality. Identified pathogenic mutations include those in the autosomal recessive AARS2 gene (Wade and Lynch, 2024) and the colony-stimulating factor-1 receptor (CSF1R) gene, the latter is relatively rare. CSF1R-positive HDLS is classified as a CSF1R-related disorder (CRD). CRD typically manifests in early adulthood with a broad spectrum of clinical symptoms, including rapidly progressive neuropsychiatric deterioration, movement and gait disorders, apraxia, epilepsy, and cortical dysfunction, ultimately leading to death. The estimated prevalence of CRD ranges from 30 to 75 cases per million (Dulski et al., 2023). Based on the reported, approximately only 300 cases of CSF1R-RD reported to date (Wade et al., 2024).

A genetic and phenotypic study of CRD patients in China (Wu et al., 2024) showed that the disease commonly presents as parkinsonism (46.0%) or cognitive impairment (38.6%), with a mean age of onset of 40.75 ± 8.58 years and a rapid disease course, with an average duration from onset to death of 2.8 ± 1.2 years. Most disease-associated CSF1R mutations (79%) are located in the tyrosine kinase domain (TKD, amino acids 582–910),with c.2381T>C/I794T identified as a hotspot mutation in Chinese CRD patients (accounting for 16.3% of cases). These mutations abrogate CSF1R kinase activity triggering a pathological cascade of microglial dysfunction (Rademakers et al., 2011), neuroinflammation, and neurodegeneration (Martins-Ferreira et al., 2025)—with microglial dysfunction emerging as the core pathological feature of CRDs. This dysfunction not only impairs central nervous system immune surveillance but may also disrupt systemic immune homeostasis via the blood-brain barrier distinguishes CRDs from other leukodystrophies (Wu et al., 2025).

Hematopoietic stem cell transplantation (HSCT) has been shown to slow CRD progression to some extent (Mochel et al., 2019):donor-derived hematopoietic stem cells can differentiate into functional microglia, replacing CSF1R-mutated, dysfunctional microglia, yet the clinical impact of CRD’s intrinsic immune vulnerability on post-transplant complications remains understudied. Invasive fungal disease (IFD) is a well-recognized HSCT complication, but the unique interplay between CSF1R mutation-driven microglial dysfunction and post-transplant iatrogenic immunosuppression—and how this synergy amplifies IFD risk—has not been clarified.

To date, there have been only 8 cases worldwide of CRDs treated with allo-HSCT, all from our clinical team (Wu et al., 2025), with only one of these cases developing invasive fungal disease (IFD) as a post-transplant complication. Building on this, we herein report the present case for the first time. The core value of this study lies in documenting the previously unreported unique clinical scenario of “CSF1R non-hotspot mutation + allo-HSCT + post-transplant IFD”. More critically, for the complex condition of this case, precisely tailored and adaptively adjusted pharmacotherapy served as the central pillar in controlling IFD and ensuring the patient’s post-transplant recovery. Beyond outlining the clinical course, we focus on elaborating the rationale behind the formulation and implementation of this individualized medication regimen, aiming to provide actionable pharmacotherapeutic references for clinicians caring for high-risk CRD patients post-HSCT.

A 42-year-old male presented in May 2024 with sudden-onset dizziness, fatigue, and dysarthria. The brain MRI shows high signals around the periventricular white matter and in the tail of the corpus callosum, with thinning of the corpus callosum, suggesting a high likelihood of hereditary leukodystrophy (Figures 1a,b). Genetic testing confirmed a CSF1R mutation, diagnosing him with HDLS. On 9 October 2024, he was admitted to hematology and underwent allogeneic HSCT (9/10 HLA match) on post-admission day +10. Post-transplant prophylaxis included levofloxacin, voriconazole, and letermovir (due to a history of CMV infection), Details of all administered medications are provided in Figure 2. All concomitant medications used throughout the patient’s post-transplant period, including their dosages, administration durations, and key drug-drug interactions, are detailed in Table 1, which allows for a clear trace of the medication adjustment logic across different treatment phases.

On post-admission day +16, the patient developed fever and right ear pain with purulent discharge. Right otomastoiditis was diagnosed by MRI (Figure 1c) and otoendoscope (Figure 1d), and meropenem was initiated. On day +20, the culture of the discharge from the right ear grew filamentous fungi. Due to persistent fever, teicoplanin and caspofungin were added for broader coverage. By day +27, fever resolved, the patient transferred from hematology to neurology, and therapy was adjusted to levofloxacin, letermovir, and voriconazole.

On day +49, the patient developed a fever and the CT showed progression of the inflammation (Figure 1f), which compared with the chest CT on first admission day (Figure 1e), given his condition worsened and renal function, meropenem and cospofungin was restarted. On day +63, thoracentesis revealed turbid brown fluid (Figure 1g), and tNGS of BALF confirmed Aspergillus flavus. Emergency antifungal therapy with voriconazole was initiated, leading to rapid symptom improvement. By day +70, chest CT showed no new lesions, and pleural effusion decreased. On day +85, the patient was rehospitalized for an upper respiratory tract infection and treated with oseltamivir (Figure 1h). By day +96, he was afebrile and discharged.

This case illustrates the challenges of managing invasive fungal disease in a patient with CSF1R-related leukoencephalopathy after allo-HSCT. The rare genetic mutation, combined with immunosuppression and CNS vulnerability, led to a highly complex medication profile. Our experience highlights the importance of precision multidrug management and close collaboration among clinical pharmacists and infectious disease specialists. Tailored antifungal therapy, guided by advanced diagnostics and pharmacokinetics, was key to clinical improvement. This case underscores the need for individualized treatment strategies in this rare, high-risk population.

This case report describes the medication-focused individualized application of existing precision tools for a patient with CSF1R gene mutation and leukodystrophy following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Due to prolonged immune reconstitution and the use of immunosuppressive drugs post-transplant, invasive fungal disease (IFD) is one of the significant complications after HSCT. The incidence of IFD is relatively higher in allo-HSCT recipients (7.4%–13.1%) and has shown an increasing trend annually. The 1-year mortality rate for patients diagnosed with IFD post-HSCT ranges from 18.0% to 65.3% (Sun et al., 2015), highlighting the importance of early diagnosis and treatment, especially empirical drug decisions.

The main pathogens causing IFD are Aspergillus, followed by Candida and Mucor (Limper et al., 2011), among antifungal agents, voriconazole shows a higher response rate against invasive Aspergillus infections. Given that the fungal pathogen causing the patient’s ear infection remained unidentified initially, voriconazole was selected as the first-line broad-spectrum antifungal treatment.

Notably, during the treatment course, the patient’s IL-6 level surged to a peak of 181.5 pg/mL (normal range: 0–7 pg/mL)—a change that directly coincided with the progression of infection: the initial ear fungal infection extended to a secondary pulmonary fungal infection. To explain this association, a reasonable inference based on existing literature, including findings from our research team’s study published in Science (Wu et al., 2025) is that microglial dysfunction may be associated with the overexpression of pro-inflammatory genes (e.g., Fyn, Stat3)—accompanied by elevated levels of peripheral pro-inflammatory factors such as IL-6—and the underexpression of phagocytosis-related genes (e.g., Hck, Ptpn6). These abnormalities, in turn, can disrupt immune surveillance and trigger the spread of infections via the blood-brain barrier and systemic circulation.

It should be noted, however, that the current study did not perform microglial function assays or immunophenotyping on the patient; thus, further research is needed to validate this proposed mechanistic link. Despite this limitation, this case remains a rare report of a CRD patient with underlying microglial dysfunction who developed breakthrough IFD after allogeneic hematopoietic stem cell transplantation (allo-HSCT)—an outcome potentially tied to the aforementioned complex mechanisms.

Against this backdrop, and guided by the core pathological logic of “CSF1R mutations drive microglial dysfunction, which further heightens IFD susceptibility and may prolong post-transplant immune recovery,” we implemented individualized clinical management for the patient: we intensified IFD monitoring by increasing the frequency of galactomannan (GM) tests from the conventional once weekly to twice weekly, and extended antifungal maintenance therapy to post-transplant day +100 (a longer duration than the typical 6–8 weeks recommended for standard allo-HSCT recipients without CSF1R-related disorders).

As pulmonary infection progressed rapidly, high-risk patients must receive definitive diagnosis and aggressive antifungal treatment to reduce mortality (Busca et al., 2021), However, in this case, despite the use of conventional broad-spectrum antifungal therapy (typically covering Aspergillus), the GM test sensitivity decreased, and culture testing took a long time with a high false-negative rate. Microscopic examination was used for rapid presumptive diagnosis but could not accurately identify the fungal species, which is crucial for antifungal drug selection, as different species show different clinical manifestations. Targeted next-generation sequencing (tNGS) does not rely on physician assumptions and can effectively assist in diagnosing complex or mixed infections by testing pathogen genetic material in samples (Zhang et al., 2024). The patient’s culture and serological tests were negative, but tNGS of the bronchoalveolar lavage (BAL) fluid sample detected Aspergillus fumigatus with high sensitivity, indirectly confirming the diagnosis. Conversely, tNGS of the ear secretion sample did not detect any fungi, possibly due to the low pathogen load or interference from open cavities, leading to missed detection. This highlights the importance of considering infection site and sample type in tNGS testing, tNGS of BAL fluid provides more accurate pathogen identification for treating pulmonary infections.

The use of antifungal drugs with different mechanisms and monitoring of immunosuppressant levels played a key role in this case. For high-risk cases with monotherapy failure, multi-site infections, or drug-resistant fungi, the combination of antifungal agents with different mechanisms is recommended (Medical Mycology Society of Chinese MEducation, A., and Chinese Society of Hematology CMA, 2023), such as echinocandins combined with voriconazole, which may improve survival rates. In this case, following breakthrough Aspergillus infection, voriconazole and caspofungin were promptly used together. Given the patient’s declining renal function, meropenem dosage was adjusted from 0.5g q8h to 1g iv q12h.

In this case, the combined use of therapeutic drug monitoring (TDM) and pharmacogenomic analysis enabled precise dose optimization of cyclosporine A and voriconazole. Post-transplant, the patient’s cyclosporine A trough levels consistently remained below the target range (87.75–130.35 ng/mL), which may be attributed to voriconazole’s inhibition of CYP3A4-mediated cyclosporine metabolism. Notably, although the patient carried the CYP2C19*1/*1 normal metabolizer genotype, the inhibitory effect of voriconazole on CYP3A4 still resulted in subtherapeutic cyclosporine exposure. Based on TDM data and dynamic liver function monitoring (Figure 3), we progressively adjusted the cyclosporine dose to 75 mg twice daily. This decision was made with reference to the recommended therapeutic window of 200–300 ng/mL in the post-HSCT setting. (Romero et al., 2002), Furthermore, this case highlights a critical therapeutic principle: when antifungal treatment inevitably alters the metabolism of immunosuppressants, maintaining effective drug concentrations through precise dose adjustments becomes essential. The precision pharmacotherapy management for invasive fungal infection in this post-transplant CRD patient was implemented based on the four-phase framework (Risk Stratification and Definition, Whole-cycle Monitoring System, Stepwise Precision Intervention, and MDT Support) illustrated in Figure 4, which provides a referable procedural paradigm for the diagnosis and treatment of similar complex cases. By detailing the clinical decision-making process, pharmacological strategies, and treatment outcomes, this report aims to offer practical guidance for the management of complex multidrug regimens and individualized pharmacotherapy in patients with CSF1R-related leukoencephalopathy following hematopoietic stem cell transplantation (HSCT).

As of the manuscript’s initial submission, the patient had completed 96 days of post-transplant follow-up and was discharged in a stable condition. To further evaluate the long-term efficacy of treatment and disease progression, we conducted an additional 3-month follow-up, extending the total post-transplant observation period to 186 days. The updated outcomes are summarized as follows: In terms of neurological function, the patient’s pre-transplant symptoms of dizziness and dysarthria were completely resolved; the Mini-Mental State Examination (MMSE) score, which was 24/30 at admission, improved to 28/30 at 186 days post-transplant, and no new movement or gait disorders emerged. For imaging findings, a brain MRI performed at 180 days post-transplant showed stable signal intensity in the periventricular white matter, with no progression of corpus callosum thinning; a chest CT scan confirmed the complete resolution of pleural effusion and fungal infiltrates that were previously present. Regarding antifungal therapy, maintenance treatment with voriconazole was discontinued at 120 days post-transplant due to the absence of invasive fungal disease (IFD) recurrence, and no long-term adverse events related to antifungal drugs (such as hepatotoxicity or visual disturbances) were observed during the entire follow-up period. These long-term follow-up data further confirm the effectiveness and safety of the individualized treatment strategy implemented for this patient, providing additional clinical evidence for the management of post-transplant complications in patients with CSF1R-related disorders.