Rare Presentation of Rosai–Dorfman Disease with Severe Lymphopenia: A Pediatric Case Report and Review of the Literature

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Cytopenias, particularly isolated lymphopenia, are particularly uncommon and poorly characterized. Hereby, we report a case of a 3-year-old boy presenting with progressive bilateral cervical lymphadenopathy and profound T- and B-cell lymphopenia. Immunophenotyping demonstrated markedly reduced CD3⁺, CD4⁺, CD8⁺, and CD19⁺ cells, low borderline level of NK-cells, and expansion of TCRγδ + double-negative (CD3⁺/CD4⁻/CD8⁻) T cells. B-cell subset analysis revealed reduced switched memory and marginal zone compartments with increased transitional B cells, suggesting immune dysregulation. Imaging confirmed extensive cervical and mediastinal lymphadenopathy. Lymph node excision biopsy showed characteristic sinus histiocytosis with emperipolesis, confirming the diagnosis of nodal RDD. No autoantibodies were detected, and bone marrow examination and genetic testing were unremarkable. Given the clinical stability and absence of organ dysfunction, the patient was conservatively managed with prophylactic antimicrobials and close surveillance, remaining stable at follow-up. A review of the literature was also conducted, identifying eight well-characterized RDD cases associated with cytopenia, involving only two cases reporting isolated lymphopenia, emphasizing the rarity of this presentation. Most cases required systemic immunosuppression due to autoimmune features or progressive disease. Detailed lymphocyte subset characterization was rarely reported. In conclusion, this case expands the immunologic spectrum of RDD and highlights isolated severe lymphopenia as a uniquely rare presentation. Comprehensive immunophenotyping is essential to distinguish RDD from primary immunodeficiency and lymphoproliferative disorders, as immune-dysregulated RDD may represent a biologically distinct subgroup with implications for precision management. RDD lymphadenopathy cytopenia histiocytosis pediatric oncology immune dysregulation Figures Figure 1 Figure 2 Introduction Rosai–Dorfman disease (RDD) is a rare condition that was first described in 1969 as sinus histiocytosis with massive lymphadenopathy (Doglioni 2021 ). Histologically, RDD is characterized by the abundance of S100 + , CD68 + , CD1a − , and CD207 − histiocytes, indicating the hallmark of emperipolesis, where intact cells like neutrophils and lymphocytes are engulfed by histiocytes (Bruce-Brand et al. 2020 ). This disease is currently classified as “histiocytoses of the R group”, encompassing familial, nodal, extranodal, neoplasia-associated, and immune-disease-associated subtypes (Emile et al. 2016). The RDD mainly affects children and young adults with male predominance. This disease typically presents with painless bilateral cervical lymphadenopathy, often associated with fever, leukocytosis, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia (Abla et al. 2018). Extranodal involvement occurs in up to 40% of cases and may affect skin, oral cavity, nasal cavity, eyes, bone, central nervous system, genitourinary system, and respiratory tract (Deen et al. 2022 ). The etiology of RDD remains unclear. Despite no clear evidence, multiple reports associate RDD with viral infections, including Epstein-Barr virus, herpes viruses, HIV, and COVID-19 (Khan et al. 2003 ; Sall et al. 2015 ; Alma et al. 2025 ). Genetic mutations in the MAPK/ERK pathway, such as BRAF, KRAS, and MAP2K1, have been reported in up to one-third of RDD cases, supporting a clonal neoplastic component in a subset of patients (Binhassan et al. 2025 ). In addition, immune dysregulation in RDD has been described but remains incompletely understood. Reported autoimmune conditions with potential association include autoimmune hemolytic anemia, immune thrombocytopenia, and antiphospholipid syndrome, hence the immune-disease-associated subtype (Vaiselbuh et al. 2014; Lopetegui-Lia et al. 2019 ). The clinical course is typically indolent, and many patients require no systemic therapy. Consensus recommendations suggest that uncomplicated, asymptomatic disease can be conservatively managed, while symptomatic, refractory, or organ-threatening disease warrants tailored intervention with options such as surgical resection for focal lesions, corticosteroids, or other systemic therapies, including chemotherapy and targeted agents, depending on severity and response (Abla et al. 2018). Hereby, we report an unusual presentation of a pediatric patient with biopsy-proven RDD associated with profound lymphopenia and significant immune dysregulation. We also review the reported cases in the literature presenting with lymphopenia in the context of RDD and discuss diagnostic considerations and implications for precision management. Case presentation An otherwise healthy 3-year-old Caucasian boy was reviewed at a two-week wait clinic presenting with a one-month history of progressive bilateral neck swellings and intermittent dysphonia. Symptoms developed following a transient viral upper respiratory illness. There was no history of fever, weight loss, night sweats, fatigue, or other lumps or swellings. His past medical history was unremarkable, apart from a self-limiting episode of chickenpox during infancy. Family history was unremarkable apart from reports of early deaths among male relatives. On physical examination, the patient was clinically well. He had extensive painless bilateral cervical and submandibular lymphadenopathy (Fig. 1 ). There was no evidence of skin lesions, hepatosplenomegaly, or other systemic abnormalities. Initial routine blood tests were within normal limits except for profound lymphopenia. Serological testing for toxoplasmosis, cytomegalovirus, Epstein–Barr virus, mumps, and HIV was negative. Immunophenotyping revealed remarkably low levels of CD3⁺, CD4⁺, and CD8⁺ T cells as well as CD19⁺ B cells with low borderline levels of CD56⁺/CD16⁺ NK cells. Double-negative T cells (CD3⁺/CD4⁻/CD8⁻) accounted for approximately 27% of T cells and were predominantly TCRγδ⁺. B-cell subset analysis demonstrated reduced switched memory B cells, markedly reduced marginal zone B cells, elevated naïve B cells, and markedly increased transitional B cells. These findings suggested immune dysregulation rather than classical autoimmune lymphoproliferative syndrome (Table 1 ). Table 1 Immunophenotyping results in the present case demonstrating pan–T-cell lymphopenia with markedly reduced CD4⁺ T cells and borderline low CD4/CD8 ratio, reduced CD19⁺ B cells with decreased switched memory and marginal zone subsets, expansion of naïve and transitional B cells, and a markedly elevated proportion of double-negative T cells (CD3⁺/CD4⁻/CD8⁻). Serum immunoglobulin levels were within the age-adjusted normal range. Summary of the reported RDD cases with cytopenia Parameter Patient Value Age-Adjusted Reference Range Interpretation CD3⁺ T cells 0.34 ×10⁹/L 1.0–3.5 ×10⁹/L Low CD4⁺ T cells 0.13 ×10⁹/L 0.5–2.0 ×10⁹/L Markedly low CD8⁺ T cells 0.137 ×10⁹/L 0.3–1.2 ×10⁹/L Low CD4/CD8 ratio ~ 0.95 1.0–3.0 Borderline low CD19⁺ B cells 0.10 ×10⁹/L 0.5–1.5 ×10⁹/L Low CD16⁺CD56⁺ NK cells 0.12 ×10⁹/L 0.1–0.8 ×10⁹/L Borderline Double-negative T cells (CD3⁺/CD4⁻/CD8⁻) 27% of CD3⁺ cells < 2% Markedly elevated Switched memory B cells Reduced Age-matched normal Decreased Marginal zone B cells Markedly reduced Age-matched normal Decreased Naïve B cells Increased proportion Age-matched normal Expanded Transitional B cells Significantly increased < 10% of B cells Markedly expanded Serum immunoglobulins Within normal range Age-matched normal No hypergammaglobulinemia Computed tomography (CT) of the neck and thorax revealed extensive bilateral cervical lymphadenopathy and right superior mediastinal lymphadenopathy (Fig. 2 ). Abdominal and pelvic ultrasonography was normal. An excisional biopsy of a right cervical lymph node demonstrated characteristic histopathological features of RDD, including sinus expansion by large histiocytes exhibiting emperipolesis (S100 + /CD68 + /CD1a − histiocytes). Bone marrow aspiration was normal, with no evidence of infiltration or malignancy. Based on clinical presentation, biochemical and immunological testing, imaging, and histopathology, a diagnosis of sporadic nodal RDD associated with severe lymphopenia and immune dysregulation was established. The case was reviewed by the UK National Histiocytosis Advisory Panel, which confirmed the diagnosis and recommended further immunological and genetic evaluation, which were unremarkable. Given the patient’s stable clinical condition and absence of extranodal disease or organ dysfunction, a conservative management approach was decided. The patient was therefore commenced on prophylactic co-trimoxazole due to significant lymphopenia and advised to avoid live vaccines. Although mTOR inhibitors such as sirolimus have been reported to be beneficial in bulky or progressive RDD, treatment was deferred because of clinical stability. Re-biopsy and further genetic analysis were planned in the event of disease progression or relapse. Regular follow-up every four months with pediatric oncology and immunology services was arranged. During follow-up, the patient remained clinically stable with persistent but non-progressive lymphadenopathy and no evidence of disease progression. Notably, at the most recent follow-up, the patient’s lymphadenopathy has completely resolved, while lymphopenia persists but has shown partial improvement, highlighting the effective conservative management approach. Discussion We report a rare presentation of a pediatric case of RDD and conduct a review of the literature, summarized in Table 2 , demonstrating that only a small number (8 cases) of well-characterized cases of RDD with lymphopenia or pancytopenia have been reported, underscoring the rarity of this presentation. Table 2 Summary of previously reported cases of RDD associated with isolated lymphopenia or pancytopenia, detailing demographic characteristics, clinical presentation, extranodal involvement, viral associations, hematologic abnormalities, immunologic dysregulation, genetic findings, bone marrow infiltration, treatment modalities, and clinical outcomes, alongside the features of the present case. Abbreviations: M, male; F, female; BM, bone marrow; COVID-19, coronavirus disease 19; CMV, cytomegalovirus; EBV, Epstein-Barr virus; URTI, upper respiratory tract infection; ESR, erythrocyte sedimentation rate; TCR. T-cell receptor; ANA, antinuclear antibody; MDS, myeloproliferative disease; IVIG, intravenous immunoglobulin; N/A, not available. Study Age/Sex Clinical presentation Extranodal disease Viral infection Hematologic Abnormality Immunologic dysregulation Genetic defect BM infiltration Treatment Outcome Petschner et al. (2001) 59/F Fatigue and generalized lymphadenopathy Pleura, pericardium, retroperitoneal, spleen, and BM No Pancytopenia ANA+, antiphospholipid IgM+, hypocomplementemia No Yes Steroids, cyclophosphamide, rituximab, IVIG, splenectomy Sustained remission Moreno et al. ( 2004 ) 9/M Cervical lymphadenopathy Oral cavity No Severe lymphopenia (↓CD3+, ↓CD4+, ↓CD8+) hypergammaglobulinemia No No Steroids, 6-mercaptopurine, methotrexate Recurrent disease Pérez et al. (2008) 45/F Fever and cervical lymphadenopathy No No Total T lymphopenia (CD4 + depletion) Polyclonal hypergammaglobulinemia and No No Immunomodulatory therapy Clinical remission and improved lymphopenia Kaffenberger et al. ( 2012 ) 60/F Fever and widespread lymphadenopathy Cutaneous and pulmonary No Pancytopenia and ↑ESR No Trisomy 8 Yes (MDS) Supportive treatment N/A Cooper et al. ( 2016 ) 1.7/M Fatigue, fever, and generalized lymphadenopathy No No Pancytopenia Positive Coombs test, lupus anticoagulant, anti-platelet antibodies No No Steroids, vinblastine, rituximab, sirolimus Sustained remission Kapoor et al. ( 2018 ) 58/M Fatigue, weight loss, and generalized lymphadenopathy CNS No Pancytopenia and ↑ESR polyclonal hypergammaglobulinemia No No 6-mercaptopurine and Prednisolone Remission (6–8 years) before CNS manifestation Gogia et al. ( 2022 ) 55/F Cervical, axillary, and inguinal lymphadenopathy Cutaneous Yes (COVID-19, CMV IgM + and IgG+, EBV IgG+) Lymphopenia, anemia, and ↑ESR ANA + and hypocomplementemia No No Methylprednisolone Clinical remission and improved lymphopenia and anemia Proskuriakova et al. ( 2024 ) Late 50s/M Fatigue and cervical and inguinal lymphadenopathy Cutaneous, pulmonary, spleen No Normal (post-treatment severe cytopenia) No KRAS (G13C), POLE, NDE1, EZH2 mutations No Antimicrobials, steroids, rituximab, lenalidomide, sirolimus Radiologic remission and improved cytopenia Present case 3/M Cervical lymphadenopathy and dysphonia No Yes (recent viral URTI) Severe lymphopenia (predominant TCRγδ + double-negative T cells) No No No Observation and prophylactic antimicrobials Stable disease RDD patients typically present with painless cervical lymphadenopathy associated with leukocytosis and, in some cases, autoimmune features (Abla et al. 2018). This case demonstrates an unusual association of RDD with severe lymphopenia and marked immune dysregulation. Although immune dysregulation and autoimmune cytopenias have been described in RDD, true lymphopenia or pancytopenia remains uncommon in this context (Moreno et al. 2004 ; Cooper et al. 2016 ). The pathophysiological link between RDD and lymphopenia is poorly understood. Possible mechanisms may include immune-mediated destruction, bone marrow infiltration/suppression, or cytokine-mediated dysregulation (Kaffenberger et al. 2012 ; Cooper et al. 2016 ; Gogia et al. 2022 ). The predominance of the double-negative TCRγδ⁺ cells, rather than TCRαβ⁺ cells, in the current case distinguished it from autoimmune lymphoproliferative syndrome (ALPS) (Matson and Yang 2020 ). Hematologic abnormalities in RDD can broadly be categorized into three phenotypic patterns: i ) normal leukocyte count or leukocytosis (the most common picture), ii ) isolated lymphopenia, or iii ) multilineage cytopenias or pancytopenia. True T-cell lymphopenia has been reported in only a few cases. Moreno et al. ( 2004 ) and Cooper et al. ( 2016 ) described a pediatric patient with severe lymphopenia (depleted CD3⁺, CD4⁺, and CD8⁺ cells) associated with hypergammaglobulinemia and a relapsing disease despite the use of immunosuppressants. Pérez et al. (2008) reported total T-cell lymphopenia with depletion of CD4 + cells and polyclonal hypergammaglobulinemia in an adult patient who had clinical remission of symptoms following immunomodulation. In both cases, there was no bone marrow infiltration, suggesting a peripheral or immune-mediated mechanism rather than primary bone marrow failure. Both reports indicate that isolated lymphopenia can occur in the context of RDD; however, neither included a detailed characterization of the broader lymphocyte subset distribution. On the other hand, multiple cases described pancytopenia in the context of RDD. Petschner et al. (2001) reported an adult RDD patient with pancytopenia in association with anti-phospholipid syndrome and immune dysregulation. Cooper et al. ( 2016 ) described recurrent autoimmune hemolytic anemia and thrombocytopenia in a pediatric RDD patient, ultimately achieving sustained remission of the disease with sirolimus. Gogia et al. ( 2022 ) presented a case of RDD associated with cytopenia and a deranged immune system following COVID-19. In addition, Kapoor et al. ( 2018 ) reported a case that progressed into neurological manifestation with pancytopenia associated with polyclonal hypergammaglobulinemia as the sole identified immunologic abnormality. These findings support the concept that RDD may coexist with or trigger systemic immune dysregulation. Similarly, autoimmune serologic abnormalities and immune-mediated cytopenias have been observed in RDD cases. Notably, all these cases with immune-mediated presentations required systemic immunosuppressive treatment. Interestingly, two of the reported cases described cytopenia in RDD without a deranged immune system. Kaffenberger et al. ( 2012 ) presented a case with pancytopenia in a patient with trisomy 8 and a concurrent myelodysplastic syndrome, whereas Proskuriakova et al. ( 2024 ) described a case with normal hematologic parameters, but cytopenia occurred only after the initiation of immunosuppressive treatment. These two cases suggest that cytopenias with no underlying immune dysfunction may occur in RDD due to a coexisting hematologic/bone marrow pathology or as a side effect of immunosuppressants rather than direct RDD-related immune dysregulation. Our patient differs significantly from previously reported cases. This current case demonstrated a profound combined T- and B-cell lymphopenia without pancytopenia, without autoimmune serologic markers, and without bone marrow suppression or infiltration. Evidence shows three potential mechanisms that may account for cytopenias in RDD: i ) direct marrow infiltration or suppression (Petschner et al. 2001), ii ) immune-mediated peripheral destruction (Cooper et al. 2016 ), and iii ) systemic immune dysregulation affecting lymphocyte homeostasis (Moreno et al. 2004 ; Pérez et al. 2008). Our case most closely aligns with the third mechanism. The absence of marrow involvement and autoimmune markers, combined with severe lymphopenia, suggests a broader adaptive immune disruption. In addition, this patient exhibited marked expansion of double-negative T cells (CD3⁺/CD4⁻/CD8⁻), predominantly of the TCRγδ + phenotype. This immunologic profile has not been clearly described in any of the previous reports. Unlike earlier lymphopenic cases, our patient did not display hypergammaglobulinemia, and detailed B-cell subset analysis revealed increased transitional B cells with reduced switched memory and marginal zone compartments, suggesting disruption of peripheral lymphocyte maturation rather than isolated depletion (Morbach et al. 2010 ). The presence of expanded double-negative T cells raises important diagnostic and management considerations, particularly with regard to ALPS. Although ALPS is characterized by TCRαβ⁺ double-negative T-cell expansion and defective FAS-mediated apoptosis, our patient lacked splenomegaly, autoimmune cytopenias, FAS mutation, and hypergammaglobulinemia. Furthermore, the predominance of TCRγδ⁺ double-negative T cells argues against classical ALPS. The distinction between RDD and ALPS is clinically important, as ALPS usually requires targeted immunomodulatory management and carries a higher risk for long-term lymphoma, warranting closer follow-up (Vignesh et al. 2017 ; Matson and Yang 2020 ). Emerging molecular data further support the biological heterogeneity of RDD. Somatic mutations involving the MAP kinase pathway have been identified in subsets of patients, which tends to be an aggressive disease (Garces et al. 2017 ; Jafri et al. 2021 ). Refractory cytopenic RDD has also been associated with KRAS and related mutations. For instance, in the case described by Proskuriakova et al. ( 2024 ), Sirolimus produced radiologic remission in a patient with severe refractory cytopenias and documented KRAS mutation. Whether immune-dysregulated RDD represents a molecularly distinct subgroup remains unknown, as most lymphopenic pediatric cases have not undergone comprehensive genetic testing. Further molecular characterization in future studies will be necessary to clarify this possibility. Notably, most reported lymphopenic or cytopenic cases required systemic and sometimes surgical (splenectomy) interventions due to progressive disease, autoimmune coexistence, or organ involvement. Systemic treatments may include corticosteroids, immunomodulators, rituximab, and mTOR inhibition. Sirolimus has demonstrated a particular efficacy in refractory immune-mediated cases (Cooper et al. 2016 ; Proskuriakova et al. 2024 ). In contrast, the current case has remained clinically stable with observation and antimicrobial prophylaxis alone. This outcome reinforces current recommendations that management in RDD should be individualized and guided by clinical picture, organ involvement, and disease progression rather than laboratory abnormalities solely. Compared with reported cases in this literature, the current case represents one of the youngest individuals described with lymphopenic RDD and is the first clearly characterized case demonstrating combined T- and B-cell lymphopenia with γδ-predominant double-negative T-cell expansion in the absence of autoimmunity or marrow infiltration. These findings expand the recognized immunologic spectrum of RDD and suggest that lymphopenic RDD presentations may constitute a biologically heterogeneous subgroup distinct from marrow-infiltrative or autoimmune-associated phenotypes. In conclusion, cytopenia in RDD is uncommon and biologically diverse. Isolated severe lymphopenia without bone marrow involvement is extremely rare and remains poorly understood. Comprehensive immunophenotyping is essential in pediatric patients presenting with lymphadenopathy and lymphopenia to distinguish RDD from primary immunodeficiency syndromes and lymphoproliferative disorders. Future studies integrating detailed immune profiling with genomic sequencing may clarify whether immune-dysregulated RDD represents a discrete molecular subtype with implications for targeted therapy and precision medicine approaches. Declarations Competing Interests The authors declare no conflicts of interest. Ethics Approval This study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. Ethical approval was not required for this single case report in accordance with the institutional policies of the University Hospitals of Leicester NHS Trust. Written informed consent for publication of this case report and any accompanying images was obtained from the patient’s legal guardians. A copy of the consent is available for review upon request. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author Contribution All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by DA, RR, and HA. The first draft of the manuscript was written by HA, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgement: Not applicable Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. References Abla O, Jacobsen E, Picarsic J, Krenova Z, Jaffe R, Emile J-F et al Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood 2018 June 28;131(26):2877–2890 Alma N, Shambu SK, Babu K (2025) Rosai-Dorfman disease presenting as a scleral nodule in a female with multisystem inflammatory syndrome post-COVID-19 infection. 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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-9153882","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":615507196,"identity":"9628775c-2aaa-4366-b9e1-06ed5063fe70","order_by":0,"name":"Doa'a Abdalla","email":"","orcid":"","institution":"University Hospitals of Leicester NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Doa'a","middleName":"","lastName":"Abdalla","suffix":""},{"id":615507197,"identity":"f960b205-88c2-442c-acfc-7a198790870e","order_by":1,"name":"Ruth Radcliffe","email":"","orcid":"","institution":"University Hospitals of Leicester NHS Trust","correspondingAuthor":false,"prefix":"","firstName":"Ruth","middleName":"","lastName":"Radcliffe","suffix":""},{"id":615507198,"identity":"2feb2125-42a5-482a-82f5-47bd5131261a","order_by":2,"name":"Hasan Asfour","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYBACAwb2gw8kKiyg3ANEaeFJNrA4I0GSFgYzgco2UrSYsx9IY7g5T0KOgf3wA2aeM0RosexJPPZw5jYJYwaeNANmnhvEOOxAQrqx5DaJxAaGHAZmng/EaDn/wEz67xyJ+gb+N8RquZFgJiHZIJHAIAGyhSiH3XiTbCBxTMKwTeKZwcE5xHjf4Hw6MCprbOT5+ZMfPnhzjAgtcMDGQFysjIJRMApGwSggBgAA+5E0Q9Z4isgAAAAASUVORK5CYII=","orcid":"","institution":"University of Leicester","correspondingAuthor":true,"prefix":"","firstName":"Hasan","middleName":"","lastName":"Asfour","suffix":""}],"badges":[],"createdAt":"2026-03-18 03:08:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9153882/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9153882/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105923453,"identity":"8ee7c158-228e-49cd-95f3-eee2934d1c62","added_by":"auto","created_at":"2026-04-01 12:58:44","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":722392,"visible":true,"origin":"","legend":"\u003cp\u003eClinical photograph demonstrating bilateral cervical lymphadenopathy, resulting in diffuse neck swelling and asymmetry.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9153882/v1/a4dc2c47aabb995bcb870073.png"},{"id":105923390,"identity":"8e34033d-bc6e-459b-97fe-b9e498ff6e49","added_by":"auto","created_at":"2026-04-01 12:58:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":254596,"visible":true,"origin":"","legend":"\u003cp\u003eContrast-enhanced CT images. The left image represents a coronal CT image of the neck demonstrating extensive bilateral cervical lymphadenopathy. The right image demonstrates a coronal CT image of the chest showing right mediastinal lymphadenopathy (yellow arrow).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9153882/v1/666315830c3b725695e00d6e.png"},{"id":106401753,"identity":"6fa7bfd6-da73-458d-bbd5-df9f16c21ace","added_by":"auto","created_at":"2026-04-08 09:09:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1565739,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9153882/v1/ae10ccc7-291a-408a-a0cb-0095e0d47c23.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rare Presentation of Rosai–Dorfman Disease with Severe Lymphopenia: A Pediatric Case Report and Review of the Literature","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRosai\u0026ndash;Dorfman disease (RDD) is a rare condition that was first described in 1969 as sinus histiocytosis with massive lymphadenopathy (Doglioni \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Histologically, RDD is characterized by the abundance of S100\u003csup\u003e+\u003c/sup\u003e, CD68\u003csup\u003e+\u003c/sup\u003e, CD1a\u003csup\u003e\u0026minus;\u003c/sup\u003e, and CD207\u003csup\u003e\u0026minus;\u003c/sup\u003e histiocytes, indicating the hallmark of emperipolesis, where intact cells like neutrophils and lymphocytes are engulfed by histiocytes (Bruce-Brand et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). This disease is currently classified as \u0026ldquo;histiocytoses of the R group\u0026rdquo;, encompassing familial, nodal, extranodal, neoplasia-associated, and immune-disease-associated subtypes (Emile et al. 2016).\u003c/p\u003e \u003cp\u003eThe RDD mainly affects children and young adults with male predominance. This disease typically presents with painless bilateral cervical lymphadenopathy, often associated with fever, leukocytosis, elevated erythrocyte sedimentation rate, and hypergammaglobulinemia (Abla et al. 2018). Extranodal involvement occurs in up to 40% of cases and may affect skin, oral cavity, nasal cavity, eyes, bone, central nervous system, genitourinary system, and respiratory tract (Deen et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe etiology of RDD remains unclear. Despite no clear evidence, multiple reports associate RDD with viral infections, including Epstein-Barr virus, herpes viruses, HIV, and COVID-19 (Khan et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Sall et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Alma et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). Genetic mutations in the MAPK/ERK pathway, such as BRAF, KRAS, and MAP2K1, have been reported in up to one-third of RDD cases, supporting a clonal neoplastic component in a subset of patients (Binhassan et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). In addition, immune dysregulation in RDD has been described but remains incompletely understood. Reported autoimmune conditions with potential association include autoimmune hemolytic anemia, immune thrombocytopenia, and antiphospholipid syndrome, hence the immune-disease-associated subtype (Vaiselbuh et al. 2014; Lopetegui-Lia et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe clinical course is typically indolent, and many patients require no systemic therapy. Consensus recommendations suggest that uncomplicated, asymptomatic disease can be conservatively managed, while symptomatic, refractory, or organ-threatening disease warrants tailored intervention with options such as surgical resection for focal lesions, corticosteroids, or other systemic therapies, including chemotherapy and targeted agents, depending on severity and response (Abla et al. 2018).\u003c/p\u003e \u003cp\u003eHereby, we report an unusual presentation of a pediatric patient with biopsy-proven RDD associated with profound lymphopenia and significant immune dysregulation. We also review the reported cases in the literature presenting with lymphopenia in the context of RDD and discuss diagnostic considerations and implications for precision management.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eAn otherwise healthy 3-year-old Caucasian boy was reviewed at a two-week wait clinic presenting with a one-month history of progressive bilateral neck swellings and intermittent dysphonia. Symptoms developed following a transient viral upper respiratory illness. There was no history of fever, weight loss, night sweats, fatigue, or other lumps or swellings. His past medical history was unremarkable, apart from a self-limiting episode of chickenpox during infancy. Family history was unremarkable apart from reports of early deaths among male relatives.\u003c/p\u003e \u003cp\u003eOn physical examination, the patient was clinically well. He had extensive painless bilateral cervical and submandibular lymphadenopathy (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was no evidence of skin lesions, hepatosplenomegaly, or other systemic abnormalities.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInitial routine blood tests were within normal limits except for profound lymphopenia. Serological testing for toxoplasmosis, cytomegalovirus, Epstein\u0026ndash;Barr virus, mumps, and HIV was negative.\u003c/p\u003e \u003cp\u003eImmunophenotyping revealed remarkably low levels of CD3⁺, CD4⁺, and CD8⁺ T cells as well as CD19⁺ B cells with low borderline levels of CD56⁺/CD16⁺ NK cells. Double-negative T cells (CD3⁺/CD4⁻/CD8⁻) accounted for approximately 27% of T cells and were predominantly TCRγδ⁺. B-cell subset analysis demonstrated reduced switched memory B cells, markedly reduced marginal zone B cells, elevated na\u0026iuml;ve B cells, and markedly increased transitional B cells. These findings suggested immune dysregulation rather than classical autoimmune lymphoproliferative syndrome (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\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\u003eImmunophenotyping results in the present case demonstrating pan\u0026ndash;T-cell lymphopenia with markedly reduced CD4⁺ T cells and borderline low CD4/CD8 ratio, reduced CD19⁺ B cells with decreased switched memory and marginal zone subsets, expansion of na\u0026iuml;ve and transitional B cells, and a markedly elevated proportion of double-negative T cells (CD3⁺/CD4⁻/CD8⁻). Serum immunoglobulin levels were within the age-adjusted normal range. \u003cb\u003eSummary of the reported RDD cases with cytopenia\u003c/b\u003e\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=\"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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatient Value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge-Adjusted Reference Range\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInterpretation\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD3⁺ T cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.34 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u0026ndash;3.5 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4⁺ T cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.13 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u0026ndash;2.0 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMarkedly low\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD8⁺ T cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.137 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.3\u0026ndash;1.2 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD4/CD8 ratio\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e~\u0026thinsp;0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u0026ndash;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBorderline low\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD19⁺ B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.10 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u0026ndash;1.5 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLow\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCD16⁺CD56⁺ NK cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.12 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1\u0026ndash;0.8 \u0026times;10⁹/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBorderline\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDouble-negative T cells (CD3⁺/CD4⁻/CD8⁻)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27% of CD3⁺ cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMarkedly elevated\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSwitched memory B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReduced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge-matched normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDecreased\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMarginal zone B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMarkedly reduced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge-matched normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDecreased\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNa\u0026iuml;ve B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIncreased proportion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge-matched normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExpanded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransitional B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSignificantly increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;10% of B cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMarkedly expanded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum immunoglobulins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWithin normal range\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge-matched normal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo hypergammaglobulinemia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eComputed tomography (CT) of the neck and thorax revealed extensive bilateral cervical lymphadenopathy and right superior mediastinal lymphadenopathy (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Abdominal and pelvic ultrasonography was normal.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAn excisional biopsy of a right cervical lymph node demonstrated characteristic histopathological features of RDD, including sinus expansion by large histiocytes exhibiting emperipolesis (S100\u003csup\u003e+\u003c/sup\u003e/CD68\u003csup\u003e+\u003c/sup\u003e/CD1a\u003csup\u003e\u0026minus;\u003c/sup\u003e histiocytes). Bone marrow aspiration was normal, with no evidence of infiltration or malignancy.\u003c/p\u003e \u003cp\u003eBased on clinical presentation, biochemical and immunological testing, imaging, and histopathology, a diagnosis of sporadic nodal RDD associated with severe lymphopenia and immune dysregulation was established. The case was reviewed by the UK National Histiocytosis Advisory Panel, which confirmed the diagnosis and recommended further immunological and genetic evaluation, which were unremarkable.\u003c/p\u003e \u003cp\u003eGiven the patient\u0026rsquo;s stable clinical condition and absence of extranodal disease or organ dysfunction, a conservative management approach was decided. The patient was therefore commenced on prophylactic co-trimoxazole due to significant lymphopenia and advised to avoid live vaccines. Although mTOR inhibitors such as sirolimus have been reported to be beneficial in bulky or progressive RDD, treatment was deferred because of clinical stability. Re-biopsy and further genetic analysis were planned in the event of disease progression or relapse. Regular follow-up every four months with pediatric oncology and immunology services was arranged. During follow-up, the patient remained clinically stable with persistent but non-progressive lymphadenopathy and no evidence of disease progression. Notably, at the most recent follow-up, the patient\u0026rsquo;s lymphadenopathy has completely resolved, while lymphopenia persists but has shown partial improvement, highlighting the effective conservative management approach.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe report a rare presentation of a pediatric case of RDD and conduct a review of the literature, summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, demonstrating that only a small number (8 cases) of well-characterized cases of RDD with lymphopenia or pancytopenia have been reported, underscoring the rarity of this presentation.\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\u003eSummary of previously reported cases of RDD associated with isolated lymphopenia or pancytopenia, detailing demographic characteristics, clinical presentation, extranodal involvement, viral associations, hematologic abnormalities, immunologic dysregulation, genetic findings, bone marrow infiltration, treatment modalities, and clinical outcomes, alongside the features of the present case. Abbreviations: M, male; F, female; BM, bone marrow; COVID-19, coronavirus disease 19; CMV, cytomegalovirus; EBV, Epstein-Barr virus; URTI, upper respiratory tract infection; ESR, erythrocyte sedimentation rate; TCR. T-cell receptor; ANA, antinuclear antibody; MDS, myeloproliferative disease; IVIG, intravenous immunoglobulin; N/A, not available.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\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=\"left\" 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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStudy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge/Sex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical presentation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eExtranodal disease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eViral infection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eHematologic Abnormality\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eImmunologic dysregulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGenetic defect\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBM infiltration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePetschner et al. (2001)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFatigue and generalized lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePleura, pericardium, retroperitoneal, spleen, and BM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eANA+, antiphospholipid IgM+, hypocomplementemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSteroids, cyclophosphamide, rituximab, IVIG, splenectomy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSustained remission\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMoreno et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2004\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCervical lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOral cavity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere lymphopenia (\u0026darr;CD3+, \u0026darr;CD4+, \u0026darr;CD8+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ehypergammaglobulinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSteroids, 6-mercaptopurine, methotrexate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRecurrent disease\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP\u0026eacute;rez et al. (2008)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFever and cervical lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal T lymphopenia\u003c/p\u003e \u003cp\u003e(CD4\u0026thinsp;+\u0026thinsp;depletion)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePolyclonal hypergammaglobulinemia and\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eImmunomodulatory therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eClinical remission and improved lymphopenia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKaffenberger et al. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2012\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFever and widespread lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCutaneous and pulmonary\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePancytopenia and \u0026uarr;ESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eTrisomy 8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eYes (MDS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSupportive treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCooper et al. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.7/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFatigue, fever, and generalized lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePositive Coombs test, lupus anticoagulant, anti-platelet antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eSteroids, vinblastine, rituximab, sirolimus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eSustained remission\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKapoor et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2018\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFatigue, weight loss, and generalized lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePancytopenia and \u0026uarr;ESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003epolyclonal hypergammaglobulinemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6-mercaptopurine and Prednisolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRemission (6\u0026ndash;8 years) before CNS manifestation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGogia et al. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55/F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCervical, axillary, and inguinal lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCutaneous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes (COVID-19, CMV IgM\u0026thinsp;+\u0026thinsp;and IgG+, EBV IgG+)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLymphopenia, anemia,\u003c/p\u003e \u003cp\u003eand \u0026uarr;ESR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eANA\u0026thinsp;+\u0026thinsp;and hypocomplementemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMethylprednisolone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eClinical remission and improved lymphopenia and anemia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProskuriakova et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLate 50s/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFatigue and cervical and inguinal lymphadenopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCutaneous, pulmonary, spleen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNormal (post-treatment severe cytopenia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eKRAS (G13C), POLE, NDE1, EZH2 mutations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eAntimicrobials, steroids, rituximab, lenalidomide, sirolimus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eRadiologic remission and improved cytopenia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePresent case\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCervical lymphadenopathy and dysphonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eYes (recent viral URTI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere lymphopenia (predominant TCRγδ\u0026thinsp;+\u0026thinsp;double-negative T cells)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eObservation and prophylactic antimicrobials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eStable disease\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRDD patients typically present with painless cervical lymphadenopathy associated with leukocytosis and, in some cases, autoimmune features (Abla et al. 2018). This case demonstrates an unusual association of RDD with severe lymphopenia and marked immune dysregulation. Although immune dysregulation and autoimmune cytopenias have been described in RDD, true lymphopenia or pancytopenia remains uncommon in this context (Moreno et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Cooper et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe pathophysiological link between RDD and lymphopenia is poorly understood. Possible mechanisms may include immune-mediated destruction, bone marrow infiltration/suppression, or cytokine-mediated dysregulation (Kaffenberger et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Cooper et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Gogia et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The predominance of the double-negative TCRγδ⁺ cells, rather than TCRαβ⁺ cells, in the current case distinguished it from autoimmune lymphoproliferative syndrome (ALPS) (Matson and Yang \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHematologic abnormalities in RDD can broadly be categorized into three phenotypic patterns: \u003cem\u003ei\u003c/em\u003e) normal leukocyte count or leukocytosis (the most common picture), \u003cem\u003eii\u003c/em\u003e) isolated lymphopenia, or \u003cem\u003eiii\u003c/em\u003e) multilineage cytopenias or pancytopenia.\u003c/p\u003e \u003cp\u003eTrue T-cell lymphopenia has been reported in only a few cases. Moreno et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2004\u003c/span\u003e) and Cooper et al. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) described a pediatric patient with severe lymphopenia (depleted CD3⁺, CD4⁺, and CD8⁺ cells) associated with hypergammaglobulinemia and a relapsing disease despite the use of immunosuppressants. P\u0026eacute;rez et al. (2008) reported total T-cell lymphopenia with depletion of CD4\u0026thinsp;+\u0026thinsp;cells and polyclonal hypergammaglobulinemia in an adult patient who had clinical remission of symptoms following immunomodulation. In both cases, there was no bone marrow infiltration, suggesting a peripheral or immune-mediated mechanism rather than primary bone marrow failure. Both reports indicate that isolated lymphopenia can occur in the context of RDD; however, neither included a detailed characterization of the broader lymphocyte subset distribution.\u003c/p\u003e \u003cp\u003eOn the other hand, multiple cases described pancytopenia in the context of RDD. Petschner et al. (2001) reported an adult RDD patient with pancytopenia in association with anti-phospholipid syndrome and immune dysregulation. Cooper et al. (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) described recurrent autoimmune hemolytic anemia and thrombocytopenia in a pediatric RDD patient, ultimately achieving sustained remission of the disease with sirolimus. Gogia et al. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) presented a case of RDD associated with cytopenia and a deranged immune system following COVID-19. In addition, Kapoor et al. (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) reported a case that progressed into neurological manifestation with pancytopenia associated with polyclonal hypergammaglobulinemia as the sole identified immunologic abnormality. These findings support the concept that RDD may coexist with or trigger systemic immune dysregulation. Similarly, autoimmune serologic abnormalities and immune-mediated cytopenias have been observed in RDD cases. Notably, all these cases with immune-mediated presentations required systemic immunosuppressive treatment.\u003c/p\u003e \u003cp\u003eInterestingly, two of the reported cases described cytopenia in RDD without a deranged immune system. Kaffenberger et al. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) presented a case with pancytopenia in a patient with trisomy 8 and a concurrent myelodysplastic syndrome, whereas Proskuriakova et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e) described a case with normal hematologic parameters, but cytopenia occurred only after the initiation of immunosuppressive treatment. These two cases suggest that cytopenias with no underlying immune dysfunction may occur in RDD due to a coexisting hematologic/bone marrow pathology or as a side effect of immunosuppressants rather than direct RDD-related immune dysregulation.\u003c/p\u003e \u003cp\u003eOur patient differs significantly from previously reported cases. This current case demonstrated a profound combined T- and B-cell lymphopenia without pancytopenia, without autoimmune serologic markers, and without bone marrow suppression or infiltration. Evidence shows three potential mechanisms that may account for cytopenias in RDD: \u003cem\u003ei\u003c/em\u003e) direct marrow infiltration or suppression (Petschner et al. 2001), \u003cem\u003eii\u003c/em\u003e) immune-mediated peripheral destruction (Cooper et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), and \u003cem\u003eiii\u003c/em\u003e) systemic immune dysregulation affecting lymphocyte homeostasis (Moreno et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; P\u0026eacute;rez et al. 2008). Our case most closely aligns with the third mechanism. The absence of marrow involvement and autoimmune markers, combined with severe lymphopenia, suggests a broader adaptive immune disruption.\u003c/p\u003e \u003cp\u003eIn addition, this patient exhibited marked expansion of double-negative T cells (CD3⁺/CD4⁻/CD8⁻), predominantly of the TCRγδ\u003csup\u003e+\u003c/sup\u003e phenotype. This immunologic profile has not been clearly described in any of the previous reports. Unlike earlier lymphopenic cases, our patient did not display hypergammaglobulinemia, and detailed B-cell subset analysis revealed increased transitional B cells with reduced switched memory and marginal zone compartments, suggesting disruption of peripheral lymphocyte maturation rather than isolated depletion (Morbach et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2010\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe presence of expanded double-negative T cells raises important diagnostic and management considerations, particularly with regard to ALPS. Although ALPS is characterized by TCRαβ⁺ double-negative T-cell expansion and defective FAS-mediated apoptosis, our patient lacked splenomegaly, autoimmune cytopenias, FAS mutation, and hypergammaglobulinemia. Furthermore, the predominance of TCRγδ⁺ double-negative T cells argues against classical ALPS. The distinction between RDD and ALPS is clinically important, as ALPS usually requires targeted immunomodulatory management and carries a higher risk for long-term lymphoma, warranting closer follow-up (Vignesh et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Matson and Yang \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEmerging molecular data further support the biological heterogeneity of RDD. Somatic mutations involving the MAP kinase pathway have been identified in subsets of patients, which tends to be an aggressive disease (Garces et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Jafri et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Refractory cytopenic RDD has also been associated with KRAS and related mutations. For instance, in the case described by Proskuriakova et al. (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), Sirolimus produced radiologic remission in a patient with severe refractory cytopenias and documented KRAS mutation. Whether immune-dysregulated RDD represents a molecularly distinct subgroup remains unknown, as most lymphopenic pediatric cases have not undergone comprehensive genetic testing. Further molecular characterization in future studies will be necessary to clarify this possibility.\u003c/p\u003e \u003cp\u003eNotably, most reported lymphopenic or cytopenic cases required systemic and sometimes surgical (splenectomy) interventions due to progressive disease, autoimmune coexistence, or organ involvement. Systemic treatments may include corticosteroids, immunomodulators, rituximab, and mTOR inhibition. Sirolimus has demonstrated a particular efficacy in refractory immune-mediated cases (Cooper et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Proskuriakova et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2024\u003c/span\u003e). In contrast, the current case has remained clinically stable with observation and antimicrobial prophylaxis alone. This outcome reinforces current recommendations that management in RDD should be individualized and guided by clinical picture, organ involvement, and disease progression rather than laboratory abnormalities solely.\u003c/p\u003e \u003cp\u003eCompared with reported cases in this literature, the current case represents one of the youngest individuals described with lymphopenic RDD and is the first clearly characterized case demonstrating combined T- and B-cell lymphopenia with γδ-predominant double-negative T-cell expansion in the absence of autoimmunity or marrow infiltration. These findings expand the recognized immunologic spectrum of RDD and suggest that lymphopenic RDD presentations may constitute a biologically heterogeneous subgroup distinct from marrow-infiltrative or autoimmune-associated phenotypes.\u003c/p\u003e \u003cp\u003eIn conclusion, cytopenia in RDD is uncommon and biologically diverse. Isolated severe lymphopenia without bone marrow involvement is extremely rare and remains poorly understood. Comprehensive immunophenotyping is essential in pediatric patients presenting with lymphadenopathy and lymphopenia to distinguish RDD from primary immunodeficiency syndromes and lymphoproliferative disorders. Future studies integrating detailed immune profiling with genomic sequencing may clarify whether immune-dysregulated RDD represents a discrete molecular subtype with implications for targeted therapy and precision medicine approaches.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\u003ch2\u003eEthics Approval\u003c/h2\u003e \u003cp\u003eThis study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments. Ethical approval was not required for this single case report in accordance with the institutional policies of the University Hospitals of Leicester NHS Trust. Written informed consent for publication of this case report and any accompanying images was obtained from the patient\u0026rsquo;s legal guardians. A copy of the consent is available for review upon request.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by DA, RR, and HA. The first draft of the manuscript was written by HA, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement:\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbla O, Jacobsen E, Picarsic J, Krenova Z, Jaffe R, Emile J-F et al Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood 2018 June 28;131(26):2877\u0026ndash;2890\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlma N, Shambu SK, Babu K (2025) Rosai-Dorfman disease presenting as a scleral nodule in a female with multisystem inflammatory syndrome post-COVID-19 infection. Taiwan J Ophthalmol 15(2):319\u0026ndash;322\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBinhassan S, Samman M, Al-Sheikh Y, Alshakweer W, Alhalouli T, Alshamlan N et al (2025) Revisiting the molecular landscape of Rosai-Dorfman disease: insights from whole exome sequencing of Saudi patients. Front Oncol 15:1556830\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBruce-Brand C, Schneider JW, Schubert P (2020) Rosai-Dorfman disease: an overview. J Clin Pathol BMJ Publishing Group 73(11):697\u0026ndash;705\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCooper SL, Arceci RJ, Gamper CJ, Teachey DT, Schafer ES (2016) Successful Treatment of Recurrent Autoimmune Cytopenias in the Context of Sinus Histiocytosis With Massive Lymphadenopathy Using Sirolimus. Pediatr Blood Cancer 63(2):358\u0026ndash;360\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDeen Iud, Chittal A, Badro N, Jones R, Haas C (2022) Extranodal Rosai-Dorfman Disease- a Review of Diagnostic Testing and Management. J Community Hosp Intern Med Perspect 12(2):18\u0026ndash;22\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoglioni C (2021) Rosai-Dorfman disease. A legacy of Professor Rosai that is still not exploited completely. Pathologica 113(5):388\u0026ndash;395\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEmile J-F, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J et al Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016 June 2;127(22):2672\u0026ndash;81\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarces S, Medeiros LJ, Patel KP, Li S, Pina-Oviedo S, Li J et al (2017) Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease. Mod Pathol 30(10):1367\u0026ndash;1377\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGogia P, Tanni F, Coca-Guzman J, Chen N, Huang Y (2022) Case report: A rare case of Rosai-Dorfman-Destombes disease after the COVID-19 infection. Front Med (Lausanne) 9:1073767\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJafri ZA, Reddy SP, Cassarino DS (2021) KRAS 117N positive Rosai-Dorfman disease with atypical features. J Cutan Pathol 48(1):147\u0026ndash;150\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaffenberger B, Darabi K, Peters S, Peters S, Kynyk J, Bechtel M (2012) Generalized eruptive histiocytomas and rosai-dorfman disease presenting concurrently in a patient with myelodysplastic syndrome. J Clin Aesthet Dermatol 5(8):42\u0026ndash;46\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKapoor A, Salunke P, Ahuja CK, Chatterjee D (2018) Spastic Quadriparesis and Communicating Hydrocephalus as Late Sequel of Rosai-Dorfman Disease: A Case Report and Review of Literature. Asian J Neurosurg 13(2):425\u0026ndash;427\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan R, Moriarty P, Kennedy S (2003) Rosai Dorfman disease or sinus histiocytosis with massive lymphadenopathy of the orbit. Br J Ophthalmol 87(8):1054\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLopetegui-Lia N, Asad SD, Jafri SI, Harrison JS (2019) Autoimmune Diseases and Rosai-Dorfman Disease Coexist More Commonly than Expected: Two Case Reports. Am J Case Rep 20:770\u0026ndash;772\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMatson DR, Yang DT (2020) Autoimmune Lymphoproliferative Syndrome: An Overview. Arch Pathol Lab Med 144(2):245\u0026ndash;251\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorbach H, Eichhorn EM, Liese JG, Girschick HJ (2010) Reference values for B cell subpopulations from infancy to adulthood. Clin Exp Immunol 162(2):271\u0026ndash;279\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoreno LB, Cavuoto MA, Kaplan B (2004) Rosai-Dorfman disease: A case report associated with oral papillomatosis and severe lymphopenia. J Allergy Clin Immunol 113(2):S126\u0026ndash;S127\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP\u0026eacute;rez EQ, Garibay GE, V\u0026aacute;zquez MIC, de la Mora MTG, Bayardo RG, Cama\u0026ntilde;o MEV (1993) [Rosai-Dorfman\u0026rsquo;s disease (sinus histiocytosis with massive lymphadenopathy): a report of a case and bibliographic review]. Rev Alerg Mex. Tecamachalco, Puebla, Mexico: ; 2008;55(5):206\u0026ndash;11\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetschner F, Walker UA, Schmitt-Gr\u0026auml;ff A, Uhl M, Peter HH [Catastrophic systemic lupus erythematosus with Rosai-Dorfman sinus histiocytosis. Successful treatment with anti-CD20/rutuximab]. Dtsch Med Wochenschr. 1946; 2001 Sept 14;126(37):998\u0026ndash;1001\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eProskuriakova E, Shunyakov L, Hoffmann S (2024) Rare presentation and unconventional treatment of Rosai-Dorfman disease. BMJ Case Rep 17(10):e262184\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSall A, Tour\u0026eacute; AO, Ndiaye FS, S\u0026egrave;ne A, Sall FB, Faye BF et al (2015) Rosai Dorfman disease diagnosed by fine-needle aspiration cytology in a young man with HIV infection. Clin Case Rep 3(10):879\u0026ndash;883\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVaiselbuh SR, Bryceson YT, Allen CE, Whitlock JA, Abla O (2014 July) Updates on histiocytic disorders. Pediatr Blood Cancer 61(7):1329\u0026ndash;1335\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVignesh P, Rawat A, Singh S (2017) An Update on the Use of Immunomodulators in Primary Immunodeficiencies. Clin Rev Allergy Immunol 52(2):287\u0026ndash;303\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"RDD, lymphadenopathy, cytopenia, histiocytosis, pediatric oncology, immune dysregulation","lastPublishedDoi":"10.21203/rs.3.rs-9153882/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9153882/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eRosai\u0026ndash;Dorfman disease (RDD) is a rare type of histiocytosis usually presenting with painless bilateral cervical lymphadenopathy and leukocytosis. Cytopenias, particularly isolated lymphopenia, are particularly uncommon and poorly characterized. Hereby, we report a case of a 3-year-old boy presenting with progressive bilateral cervical lymphadenopathy and profound T- and B-cell lymphopenia. Immunophenotyping demonstrated markedly reduced CD3⁺, CD4⁺, CD8⁺, and CD19⁺ cells, low borderline level of NK-cells, and expansion of TCRγδ\u003csup\u003e+\u003c/sup\u003e double-negative (CD3⁺/CD4⁻/CD8⁻) T cells. B-cell subset analysis revealed reduced switched memory and marginal zone compartments with increased transitional B cells, suggesting immune dysregulation. Imaging confirmed extensive cervical and mediastinal lymphadenopathy. Lymph node excision biopsy showed characteristic sinus histiocytosis with emperipolesis, confirming the diagnosis of nodal RDD. No autoantibodies were detected, and bone marrow examination and genetic testing were unremarkable. Given the clinical stability and absence of organ dysfunction, the patient was conservatively managed with prophylactic antimicrobials and close surveillance, remaining stable at follow-up. A review of the literature was also conducted, identifying eight well-characterized RDD cases associated with cytopenia, involving only two cases reporting isolated lymphopenia, emphasizing the rarity of this presentation. Most cases required systemic immunosuppression due to autoimmune features or progressive disease. Detailed lymphocyte subset characterization was rarely reported. In conclusion, this case expands the immunologic spectrum of RDD and highlights isolated severe lymphopenia as a uniquely rare presentation. Comprehensive immunophenotyping is essential to distinguish RDD from primary immunodeficiency and lymphoproliferative disorders, as immune-dysregulated RDD may represent a biologically distinct subgroup with implications for precision management.\u003c/p\u003e","manuscriptTitle":"Rare Presentation of Rosai–Dorfman Disease with Severe Lymphopenia: A Pediatric Case Report and Review of the Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-01 12:58:14","doi":"10.21203/rs.3.rs-9153882/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-13T17:39:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-10T19:03:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-10T17:22:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"79433907516205192038092235481861494650","date":"2026-04-10T04:40:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222696299030579284316833986573881496283","date":"2026-04-09T19:20:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T19:59:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-08T12:46:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"144597792165144475986982287853868039012","date":"2026-04-08T12:15:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"32818178545702000766058003566048225297","date":"2026-04-07T07:20:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-07T04:09:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"321061332130443617747688982247090727575","date":"2026-04-07T04:03:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"104474179308681573327120539978567822608","date":"2026-04-07T03:06:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"27292490255317802631997043879480100189","date":"2026-04-06T17:38:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315409750409023019938815607710948261360","date":"2026-04-06T17:22:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"179590357417415362337967846677766137809","date":"2026-04-06T14:10:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"105918570326066158892335279396117194782","date":"2026-04-05T11:18:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35040208048399731628269102854945931070","date":"2026-04-05T09:52:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"241447578585336862435570057758122096831","date":"2026-03-31T20:27:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-30T14:44:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-30T03:41:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-27T14:18:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cancer Research and Clinical Oncology","date":"2026-03-19T23:48:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cancer-research-and-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jocr","sideBox":"Learn more about [Journal of Cancer Research and Clinical Oncology](https://www.springer.com/journal/432)","snPcode":"432","submissionUrl":"https://submission.nature.com/new-submission/432/3","title":"Journal of Cancer Research and Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7239ce17-412f-4fca-9297-5f4c1ecf80d8","owner":[],"postedDate":"April 1st, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T15:23:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-01 12:58:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9153882","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9153882","identity":"rs-9153882","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}