RARE DISEASE
X-linked lymphoproliferative disease due to SAP deficiency
X-linked lymphoproliferative disease due to SAP deficiency
X-linked lymphoproliferative disease due to SAP deficiency
Synonyms: X-linked lymphoproliferative disease due to SH2 domain containing 1A protein deficiency, X-linked lymphoproliferative disease due to SH2D1A deficiency, X-linked lymphoproliferative disease due to Signaling lymphocyte activation molecule-associated protein deficiency, X-linked lymphoproliferative syndrome type 1, XLP1
Synonyms: X-linked lymphoproliferative disease due to SH2 domain containing 1A protein deficiency, X-linked lymphoproliferative disease due to SH2D1A deficiency, X-linked lymphoproliferative disease due to Signaling lymphocyte activation molecule-associated protein deficiency, X-linked lymphoproliferative syndrome type 1, XLP1
Synonyms: X-linked lymphoproliferative disease due to SH2 domain containing 1A protein deficiency, X-linked lymphoproliferative disease due to SH2D1A deficiency, X-linked lymphoproliferative disease due to Signaling lymphocyte activation molecule-associated protein deficiency, X-linked lymphoproliferative syndrome type 1, XLP1
Drug discovery
119
papers
On emerging therapies
Overview
X-linked lymphoproliferative disease due to SAP deficiency (XLP1) is a rare X-linked recessive immunodeficiency caused by SH2D1A mutations, impairing cytotoxic lymphocyte regulation and EBV response. Key manifestations include EBV-triggered hemophagocytic lymphohistiocytosis (HLH), lymphoma, hypogammaglobulinemia, and vasculitis. Untreated, mortality exceeds 70% by age 10. Hematopoietic stem cell transplantation (HSCT) remains curative if performed early, while pre-transplant strategies focus on controlling HLH and preventing EBV complications [1][4][9][14].
Therapies
Curative: Allogeneic HSCT (80% survival; reduced to 50% with pre-transplant HLH) [4][5]
Pre-transplant management: Rituximab (anti-CD20) for EBV suppression, IVIG for hypogammaglobulinemia, and HLH-directed therapy (dexamethasone/etoposide) [5][7][14]
Monitoring: Avoid live vaccines; EBV PCR surveillance [9][10]
Categories: rare genetic diseases, rare immunological diseases, rare neoplastic diseases
Research Papers
119 drug discovery papers about X-linked lymphoproliferative disease due to SAP deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
119 drug discovery papers about X-linked lymphoproliferative disease due to SAP deficiency, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-20 | Epstein Barr Virus–Driven Hodgkin Lymphoma in a Patient with X-linked Lymphoproliferative Disease Type 1 and XYY Karyotype: Rare Association
Introduction X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency caused by pathogenic variants in the SH2D1A gene, characterized by a dysregulated immune response to Epstein–Barr virus (EBV), hypogammaglobulinemia, a markedly increased risk of hemophagocytic lymphohistiocytosis (HLH) and EBV-driven lymphoproliferation, while Hodgkin lymphoma (HL) represents an exceptionally rare complication. Case Presentation We report a male patient diagnosed with XLP1 at the age of six following his first episode of HLH, with confirmation of a pathogenic SH2D1A variant. Cytogenetic analysis revealed a 47, XYY karyotype. The patient remained clinically stable until the age of 28, when he experienced a new episode of EBV reactivation-associated HLH. Treatment with dexamethasone and immunomodulatory doses of intravenous immunoglobulin (IVIG) resulted in prompt clinical improvement, and a long-term IVIG replacement was initiated due to hypogammaglobulinemia. Four months later, the patient presented with severe abdominal pain, fever, pancytopenia, splenomegaly, hyperferritinemia, and markedly elevated soluble IL-2 receptor levels (9,840 IU/mL), consistent with a third episode of EBV-associated HLH (viral load 207,000 viral copies/mL). Treatment was initiated according to the HLH-2014 protocol, including dexamethasone, immunomodulatory IVIG, and rituximab. Despite transient improvement, clinical and laboratory deterioration occurred, prompting escalation with high-dose methylprednisolone pulses, leading to significant clinical improvement. Interestingly, bone marrow biopsy performed before treatment revealed infiltration consistent with HL. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated active disease in the spleen and bone marrow, establishing a stage IVA diagnosis. Chemotherapy with the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) protocol was initiated. After two cycles, interim FDG-PET/CT showed complete metabolic remission (Deauville score 1/2), and treatment continued with four cycles of AVD, according to European Society for Medical Oncology (ESMO) guidelines. Key Messages for Clinical Practice This case illustrates that XLP1 patients remain at lifelong risk for EBV-driven HLH and rare lymphomas, and emphasizes that early recognition, vigilant monitoring, and prompt targeted therapy, including rituximab and tailored chemotherapy, can achieve complete remission, even in this high-risk population.
2025-04-25 | Addition of Thiotepa to Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Reduces Secondary Graft Failure in Allogeneic HSCT for Inborn Errors of Immunity
Introduction Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimen is associated with a high incidence of mixed chimerism and secondary graft failure in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for inborn errors of immunity (IEI). We hypothesized that addition of thiotepa to this regimen would reduce secondary graft failure without increasing toxicity in children and young adults undergoing allogenic HSCT for IEI. Methods We retrospectively reviewed charts of patients undergoing allogenic HSCT for IEI who received alemtuzumab (starting on day -14), fludarabine (150 mg/m2 or 5 mg/kg over days -8 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg on day -3) containing RIC regimen with the addition of thiotepa (200 mg/m2 on day -2). Mixed chimerism and low-level mixed chimerism were defined as whole blood donor chimerism <95% and <50%, respectively, on two consecutive measures within a 2-week period. Results Thirty-one patients underwent allogeneic HSCT at a median age of 1.7 years (0.3-21 yrs). Patient demographics are outlined in Table 1. All patients engrafted at a median of 12 days (range, 8-17 days). The incidence of mixed chimerism was 0% (0/31), 20% (5/25), and 46% (7/15) upon engraftment at day +100 and one-year post-HSCT, respectively. Incidence of low-level mixed chimerism was 0% (0/25) and 6.6% (1/15) at day +100 and one-year post-HSCT, respectively. Three (9.6%) patients required a secondary intervention (2 CD34 selected boost and 1 second HSCT). Two (6.4%) patients developed sinusoidal obstruction syndrome, and 11 (35%) patients developed thrombotic microangiopathy. Six (19%) patients developed grade I-II skin GVHD, with none developing grade III-IV GVHD. One (3.2%) patient developed limited chronic GVHD. Thirteen of 31 (42%) patients had viral reactivation requiring treatment, with CMV (54%), EBV (54%), and adenovirus (15%) being the most common. Twenty-six (84%) patients are surviving at median follow-up of 10 months (range 2m-4y 2m) post-HSCT. Table 1.Patient demographics (n = 31).Median age at transplant (range)1y 8m (4m-21y 11m)Median Follow up (range)10 m (2m-4y 2m)GenderMale19 (61%)Female12 (39%)DiagnosisHLH19 (61%)sJIA5 (16%)XLP1 (3.2%)XIAP1 (3.2%)LRBA deficiency1 (3.2%)XMEN1 (3.2%)SCID1 (3.2%)Griscelli1 (3.2%)Early onset IBD1 (3.2%)Donor RelationshipRelated21 (68%)Unrelated10 (32%)HLA Match10/1021 (68%)9/106 (19%)7/101 (3%)6/103 (10%)Stem cell sourceBM23 (74%)PBSCs, CD34 selected5 (16%)PBSCs, alpha beta depleted3 (10%)GVHD prophylaxisCSA/MMF11 (35.5%)CSA/MMF/Abatacept10 (32%)CD34 selection5 (16%)Alpha-beta T cell depletion3 (10%)CSA/MMF/PT-Cy2 (6.5%) Conclusion Addition of thiotepa to a RIC regimen containing fludarabine, alemtuzumab, and melphalan reduces secondary graft failure without increasing toxicity in children and young adults undergoing allogenic HSCT for IEI. Longer duration of follow-up is needed to assess durability of donor chimerism.
2024-05-01 | X-Linked Lymphoproliferative Disease Type 2 With Activation of Hemophagocytic Lymphohistiocytosis Secondary to Epstein-Barr Virus Infection
Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially life-threatening syndrome. It is best described as uncontrolled immune system activation leading to hemophagocytosis. Our case report aims to present a practical approach, discuss the challenges in the diagnosis and management of HLH, and to shed light on the X-linked lymphoproliferative disease type 2 (XLP-2) gene, STXBP2 gene (as a carrier), and Epstein-Barr virus (EBV) infection in relation to HLH. This is a 2-year-8-month-old Saudi boy, who presented to the emergency department with fever for more than 7 days, not associated with any other major complaints. During the first couple of days of admission, primary results showed hyperferritinemia, low fibrinogen, anemia, high inflammatory markers, high D-dimer, and increasing liver enzymes and triglycerides. The patient fulfilled the diagnostic criteria of HLH on the third day of admission. Further investigations revealed a genetic mutation in XLP-2 gene, STXBP2 gene (as a carrier) and EBV infection causing HLH. HLH-94 protocol was used for management. The patient had an excellent clinical outcome, unexpectedly, by only using dexamethasone, with complete remission and no recurrence up to date. HLH is not frequently encountered in daily practice. However, it can be fatal. This case report describes a unique case of XLP-2, STXBP2 carrier with extreme EBV infection and activation of HLH, who was successfully brought into remission by partial application of HLH-94 protocol and careful clinical and laboratory monitoring. The diagnosis and management of HLH can be challenging. However, a reasonable clinical judgment can improve the outcomes. Int J Clin Pediatr. 2024;13(1):26-33 doi: https://doi.org/10.14740/ijcp525
2024-03-22 | CXCR4: from B-cell development to B cell–mediated diseases
Chemokine receptors are members of the G protein–coupled receptor superfamily. The C-X-C chemokine receptor type 4 (CXCR4), one of the most studied chemokine receptors, is widely expressed in hematopoietic and immune cell populations. It is involved in leukocyte trafficking in lymphoid organs and inflammatory sites through its interaction with its natural ligand CXCL12. CXCR4 assumes a pivotal role in B-cell development, ranging from early progenitors to the differentiation of antibody-secreting cells. This review emphasizes the significance of CXCR4 across the various stages of B-cell development, including central tolerance, and delves into the association between CXCR4 and B cell–mediated disorders, from immunodeficiencies such as WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome to autoimmune diseases such as systemic lupus erythematosus. The potential of CXCR4 as a therapeutic target is discussed, especially through the identification of novel molecules capable of modulating specific pockets of the CXCR4 molecule. These insights provide a basis for innovative therapeutic approaches in the field.
2022-12-15 | Allosteric inhibition of SHP2 rescues functional T-cell abnormalities in SAP deficiency.
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency arising from SH2D1A mutations leading to loss of SLAM-associated protein (SAP). SAP is an intracellular adaptor protein that binds to SLAM family receptors and is expressed in specific lymphoid lineages. In T cells, SAP relays activatory signals from the T-cell receptor but in its absence SH2 containing protein tyrosine phosphase-1 (SHP1), SH2 containing protein tyrosine phosphase-2 (SHP2), and SH2 containing inositol 5'-phosphatase proteins (SHIP) induce T-cell inhibitory signals leading to abnormal T-cell responses. This results in severe clinical manifestations including immune dysregulation, dysgammaglobulinemia, lymphoma, and hemophagocytic lymphohistiocytosis. Current treatment relies on supportive therapies including immunoglobulin replacement and symptom-directed therapy, with hematopoietic stem cell transplant offering the only curative option. As most XLP symptoms are due to defective T-cell function, this study investigated whether inhibition of SHP2 can restore cellular function in the absence of SAP. Healthy donor and XLP patient T cells were activated with anti-CD3/CD28 in T-cell media supplemented with a SHP2 inhibitor (RMC-4550 in vitro for 24 hours) and functional assays were performed to assess follicular TH (TFH) cell function, CD8 cytotoxicity, and sensitivity to restimulation-induced cell death. Additionally, SAP-deficient (SAPy/-) mice were treated with RMC-4550 before T-cell mediated challenge with 4-hydroxy-3-nitrophenylacetly conjugated chicken gammaglobulin and subsequent assessment of humoral immunity analyzing TFH cell population, germinal center formation, and antigen-dependent immunoglobulin secretion. This study shows that the use of RMC-4550 restores T-cell function in XLP patient cells and a SAPy/- model, demonstrating restoration of TFH cell function through immunoglobulin and cytokine secretion analysis alongside rescue of cytotoxicity and restimulation-induced cell death. These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for patients with XLP.
gene therapies
2025-10-08 | Image 2_X-linked lymphoproliferative disease with initial onset of neurological symptoms: a case and literature review.jpg
X-linked lymphoproliferative syndrome type 1 (XLP-1) is a life-threatening X-linked recessive immunodeficiency classically characterized by susceptibility to Epstein–Barr virus (EBV), hypogammaglobulinemia, and lymphoma. While neurological involvement can occur, it is exceptionally rare as the initial and predominant manifestation. This case report details a novel presentation of XLP-1 in a 4-year-old boy who presented with acute, initial neurological symptoms (sudden fever, headache, and vomiting) in the absence of typical immune dysregulation features. Whole-exome sequencing (WES) identified a hemizygous variant in the SH2D1A gene (c.1A>G, p. Met1Val), predicted as damaging/disease-causing by MutationTaster (probability = 0.993) and PolyPhen-2 (probability = 0.992). Meanwhile, according to the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, this variant met four evidence criteria (PVS1_Moderate+ +PM2_Moderate+PP3+PP5) and was classified as pathogenic. Structural analysis leveraging the AlphaFold protein structure database demonstrated that this variant disrupts the Kozak consensus sequence and splice site, critically impairing start codon recognition and translation initiation, thereby explaining the loss of functional SLAM-associated protein (SAP) protein expression. This case, along with a focused review of the literature, underscores that XLP-1 rarely presents primarily with neurological symptoms, broadening the clinical phenotype spectrum and emphasizing the need for early genetic evaluation in children with unexplained acute neurological presentations, even in the absence of overt immunodeficiency signs. This finding provides crucial clinical data for a more comprehensive understanding of XLP-1.
2025-09-05 | Severe Oral Lichen Planus Masking a Primary Immunodeficiency: X-Linked Lymphoproliferative Disease Type 1 (XLP-1).
A 14-year-old boy was initially diagnosed with erosive oral lichen planus based on clinical and histopathological findings. However, the atypical clinical course and resistance to immunosuppressive therapy raised suspicion for an autoinflammatory disorder or inborn error of immunity. Genetic testing revealed a pathogenic SH2D1A mutation, confirming X-linked lymphoproliferative disease type 1 (XLP-1) in the absence of Epstein-Barr virus exposure. This case highlights oral mucosal lesions as a potential early, EBV-independent manifestation of XLP-1 and emphasizes the importance of considering monogenic immune disorders in persistent, treatment-refractory mucosal disease.
2025-06-27 | X-linked lymphoproliferative disease type 1: a clinical and genetic update.
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a primary immunodeficiency disorder linked to the X chromosome. In 1998, SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), was identified as the first pathogenic gene associated with XLP. To date, more than 100 mutation sites in this gene have been documented. The disease is associated with infection with Epstein-Barr virus (EBV) and characterized by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobulinemia, and lymphomas. Pathogenesis is intricately associated with cell type-specific SAP-SLAM signaling pathways. Particularly, the immune cell defects involve impaired T cell-B cell interactions, reduced cytotoxicity of Natural Killer (NK) cells, and abnormal development of Natural Killer T (NKT) cells. These factors collectively increase susceptibility to EBV and drive clinical manifestations in XLP type 1 (XLP1) patients. Although establishing a definitive correlation between specific genotypes and clinical phenotypes remains challenging, emerging evidence suggests a potential association. This underscores the critical need for further large-scale studies to elucidate this relationship. Given the current understanding of the pathophysiological mechanisms associated with XLP1, specific treatments to normalize SAP expression and restore immune tolerance in XLP1 patients play an important role. In addition to the necessity for long-term studies to verify the efficacy and safety of hematopoietic stem cell transplantation (HSCT), gene therapies currently under development, along with other emerging treatments, exhibit substantial promise for future clinical applications.
2024-09-23 | Lentiviral vectors for precise expression to treat X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease (XLP1) results from SH2D1A gene mutations affecting the SLAM-associated protein (SAP). A regulated lentiviral vector (LV), XLP-SMART LV, designed to express SAP at therapeutic levels in T, NK, and NKT cells, is crucial for effective gene therapy. We experimentally identified 34 genomic regulatory elements of the SH2D1A gene and designed XLP-SMART LVs to emulate the lineage and stage-specific control of SAP. We screened them for their on-target enhancer activity in T, NK, and NKT cells and their off-target enhancer activity in B cell and myeloid populations. In combination, three enhancer elements increased SAP promoter expression up to 4-fold in on-target populations in vitro. NSG-Tg(Hu-IL15) xenograft studies with XLP-SMART LVs demonstrated up to 7-fold greater expression in on-target cells over a control EFS-LV, with no off-target expression. The XLP-SMART LVs exhibited stage-specific T and NK cell expression in peripheral blood, bone marrow, spleen, and thymic tissues (mimicking expression patterns of SAP). Transduction of XLP1 patient CD8+ T cells or BM CD34+ cells with XLP-SMART LVs restored restimulation-induced cell death and NK cytotoxicity to wild-type levels, respectively. These data demonstrate that it is feasible to create a lineage and stage-specific LV to restore the XLP1 phenotype by gene therapy.
2019-08-02 | Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects. CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.
cell therapies
2025-10-22 | The neurologic face of X-linked lymphoproliferative syndrome type 1: a systematic review.
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals. The online version contains supplementary material available at 10.1186/s13023-025-04057-9.
2023-02-28 | Clinical Case of X-Linked Lymphoproliferative Syndrome Burdened with Hemophagocytic Lymphohistiocytosis and Crohn's Disease
Background . X-linked lymphoproliferative (XLP) syndrome is hereditary disease with the incidence of 1-3 per 1 million born boys. This clinical case demonstrates a rare picture of XLP type 2 manifestation without prior Epstein-Barr virus. Clinical case description . Boy D., 15 years old, was admitted to Morozovskaya Children's City Hospital with complaints on fever, abdominal pain, loose stools, weight loss. The past medical history included hemophagocytic syndrome (remission) and acute erythema nodosum. We have performed several studies: abdominal ultrasound (hepatomegaly, dynamic changes in the intestine: parts of the small intestine were enlarged and walls were thickened, mass peristalsis, walls of transverse colon and descending colon are thickened up to 5 mm, mesenteric lymphadenopathy), rectosigmoidoscopy (high-activity ulcerative proctosigmoiditis corresponds to Crohn's disease), biochemical and clinical blood tests (active hemophagocytic syndrome), coagulogram (secondary hypocoagulation), myelogram (no data on hemoblastosis or aplastic condition). Virological blood tests (CMV, EBV, HHV-VI): negative. Laboratory and instrumental tests have revealed recurrence of hemophagocytic syndrome and Crohn's disease. The child was consulted by rheumatologist, hematologist, gastroenterologist, geneticist, neurologist, and clinical pharmacologist. The primary immune deficiency disease was suspected in this patient due to his medical history. Molecular genetic study was performed (deletion including the XIAP gene was revealed) and the diagnosis of primary immune deficiency was verified: X-linked lymphoproliferative syndrome type 2. Thus, allogeneic haematopoietic stem cell transplantation (HSCT) was performed. Conclusion . XLP diagnosis and management require multidisciplinary approach. The early diagnosis is crucial due to the high risk of secondary complications development that can significantly worsen the disease's prognosis. Allogeneic HSCT is the only effective treatment for the disease.
2022-10-29 | From inborn errors of immunity to lymphoma: A hematologist’s point of view
After infections, malignancies, lymphomas especially, are the second most frequent cause of death in patients with inborn errors of immunity. Factors predetermining the appearance and aggressiveness of lymphomas include gene defects, defects of immune surveillance and regulation as well as infections with oncogenic viruses. Aggressive non-Hodgkin lymphomas, mostly diffuse large B-cell and Bukit subtypes are predominant in deoxyribonucleic acid repair defects, while Hodgkin lymphoma becomes equally present in patients with defects of immune regulation. Marginal zone and mucosa-associated lymphoid tissue lymphomas, appear to be frequent in defects of antibody production, especially in patients with common variable immune deficiency. The prevalence of Epstein-Barr virus may vary within entities, but there is no entity without at least a few cases of lymphoma and Epstein-Barr virus co-infection. Standard treatment of lymphomas associated with deoxyribonucleic acid repair defects and severe combined deficiencies, is stem cell transplantation. Lymphomas in inborn errors of immunity with a less severe clinical presentation, should be treated with immunochemotherapy and monoclonal antibodies (Brentuximab, Rituximab) wherever feasible. There is no data about the usefulness of checkpoint inhibitors, bi-specific antibodies and T-cells with chimeric antigen receptor. Allogeneic stem cell transplantation represents a major indication for treatment of relapse/refractory lymphomas in any inborn error of immunity. Potential benefit of therapy with Chimeric antigen receptor Natural-killer cells in lymphomas associated with inborn errors of immunity, remains to be seen in future studies.
2022-04-18 | Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.
Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.
2022-01-05 | Two Clonally Distinct B-Cell Lymphomas Reveal the Diagnosis of XLP1 in a Male Child and His Asymptomatic Male Relatives: Case Report and Review of the Literature.
X-linked lymphoproliferative disease type 1 (XLP1) is a primary immunodeficiency disorder caused by pathogenic variants in the SH2D1A gene (SH2 domain containing protein 1A). Patients with XLP1 may present acutely with fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, and/or B-cell non-Hodgkin lymphoma (B-NHL). We report a boy who developed 2 clonally distinct B-NHL 4 years apart and was found to have previously unrecognized XLP1. The report highlights the importance of clonal analysis and XLP1 testing in males with presumed late recurrences of B-NHL, and the role of allogeneic stem cell transplant (allo-SCT) in XLP1 patients and their affected male relatives.
antibodies
2025-11-03 | Hemophagocytic lymphohistiocytosis of the ocular adnexal mimicking orbital cellulitis in a patient with unknown X-linked lymphoproliferative syndrome type 1 (XLP1): Case report and literature review.
A 5-year-old boy presented with severe acute bilateral periorbital edema. Initial misdiagnosis was made as preseptal orbital cellulitis, and he failed to respond to conventional antibiotic therapy. Magnetic resonance imaging revealed thickening of the anterior orbital adipose tissue bilaterally, with hyperintensity on T2-weighted imaging. The biopsy unveiled lymphoma-associated hemophagocytic syndrome, specifically Epstein-Barr virus related. The patient was administered rituximab, resulting in a significant amelioration. A family history, coupled with genetic investigation, ultimately led to the diagnosis of X-linked lymphoproliferative syndrome type 1 due to a large deletion of exons 2-4 of *SH2D. Reported ocular manifestation of XLP1 includes retinal hemorrhages, disc edema, acute posterior multifocal placoid pigment epitheliopathy, and macular edema. No ocular adnexal involvement has been previously reported. This case documents a case of XLP1 syndrome affecting the ocular adnexa and emphasizes the critical need to consider underlying immunodeficiencies in patients who do not respond to conventional therapies.
2025-04-25 | Insights into EBV Infection in an Adult with X-Linked Lymphoproliferative Syndrome
Introduction X-linked lymphoproliferative disease (XLP) is a rare inborn error of immunity (IEI) characterized by increased susceptibility to Epstein–Barr Virus (EBV) and other features of immune dysregulation. We present a case of XLP1, diagnosed in a 37-year-old male with EBV viremia treated with nivolumab. Case The proband was diagnosed with common variable immunodeficiency (CVID) and started on IVIG at age 8. Infections were recurrent pneumonias and an episode of septic hip arthritis. He remained infection free over the next 3 decades until presenting with Evans syndrome at age 37, which was initially treated with prednisone. Shortly after, his course was complicated with hepatic and brain abscesses and liver decompensation. Thus, he was referred to our service for workup. Genetic testing revealed the diagnosis of XLP1 (SH2D1A c.138-2A>G). He was found to have EBV viremia, and a liver biopsy suggested EBV hepatitis. He was not a liver transplant candidate due to concern of sepsis given his immunosuppression and IEI. Hematopoietic stem cell transplant (HSCT) was not offered due to high risk of mortality. Despite treatment with rituximab, his repeat EBV titers continued to rise. Virus-specific T cell therapy was pursued; however, the patient was clinically too unstable to be transferred for treatment to the United States from Canada. He was given one nivolumab dose, significantly reducing his viremia. He ultimately succumbed to sepsis and respiratory failure. EBV is the leading cause of mortality in patients with XLP who forego HSCT. Rituximab has been well-documented in the treatment of EBV. We present a patient with an EBV susceptibility syndrome and progressive viremia, who responded well to one dose of nivolumab which significantly reduced his EBV viral load. Despite limited literature, nivolumab may play a significant role in the treatment of certain EBV-associated conditions, particularly in patients with IEIs. In conclusion, nivolumab should be considered for any patient with an overwhelming EBV infection. Severe EBV-induced disease is an unexpected finding in an individual with CVID and warrants genetic testing to exclude other primary immunodeficiencies. Treatment options for EBV susceptibility syndromes need further exploration and accessibility.
2024-04-03 | Case report: EBV-related eye orbits and sinuses lymphohistiocytic infiltration responsive to rituximab in a patient with X lymphoproliferative syndrome type 1
Background and aims X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A , encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. Methods We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein–Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. Results The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. Conclusion We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.
2023-09-01 | X‐linked lymphoproliferative syndrome associated with Epstein–Barr virus encephalitis and lymphoproliferative disorder
When treating patients with EBV encephalitis, the possibility of XLP should be considered. Once the diagnosis of XLP is made, aggressive treatment such as rituximab, and other immunosuppressive agents are desired for rapid transition to HSCT.
2022-08-23 | Fatal X-linked lymphoproliferative disease type 1-associated limbic encephalitis with positive anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody.
X-linked lymphoproliferative disease type 1 (XLP1) is a rare monogenic immune dysregulation disorder caused by a deficiency of a signaling lymphocyte activation molecule-associated protein (SAP). While many patients with XLP1 present with fatal hemophagocytic lymphohistiocytosis upon Epstein Barr virus (EBV) infection, a small fraction present with limbic encephalitis in the absence of EBV infection. It is poorly understood why SAP deficiency may cause limbic encephalitis in XLP1. A 12-year-old boy presented with seizures, changes in personality, memory loss, and cognitive deficits during treatment for interstitial pneumonia. A diagnosis of limbic encephalitis was made. Despite treatment against CD8+ T cell-mediated autoimmunity with intravenous methylprednisolone, dexamethasone, intravenous immunoglobulin, plasma exchange, cyclosporine, weekly etoposide, mycophenolate mofetil, and adalimumab, encephalitis progressed until the patient died after one month of treatment intitiation. Post-mortem genetic testing revealed a de novo SH2D1A truncating mutation. Tests for EBV infection were negative. Initial spinal fluid revealed markedly elevated protein levels, mild pleocytosis, and elevation of two chemokines (C-X-C motif chemokine ligand [CXCL] 10 and CXCL 13). Moreover, initial spinal fluid was tested positive for anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) autoantibody. In XLP1-associated limbic encephalitis, anti-AMPAR autoantibody production by the dysregulated immune system due to SAP deficiency might be a pathogenic mechanism of central nervous system manifestations. In addition to the standard treatment for XLP1, targeted treatment against B-cell-mediated immunity might be indicated for patients with XLP1-associated limbic encephalitis.
small molecules
2026-08-20 | Epstein Barr Virus–Driven Hodgkin Lymphoma in a Patient with X-linked Lymphoproliferative Disease Type 1 and XYY Karyotype: Rare Association
Introduction X-linked lymphoproliferative disease type 1 (XLP1) is a rare primary immunodeficiency caused by pathogenic variants in the SH2D1A gene, characterized by a dysregulated immune response to Epstein–Barr virus (EBV), hypogammaglobulinemia, a markedly increased risk of hemophagocytic lymphohistiocytosis (HLH) and EBV-driven lymphoproliferation, while Hodgkin lymphoma (HL) represents an exceptionally rare complication. Case Presentation We report a male patient diagnosed with XLP1 at the age of six following his first episode of HLH, with confirmation of a pathogenic SH2D1A variant. Cytogenetic analysis revealed a 47, XYY karyotype. The patient remained clinically stable until the age of 28, when he experienced a new episode of EBV reactivation-associated HLH. Treatment with dexamethasone and immunomodulatory doses of intravenous immunoglobulin (IVIG) resulted in prompt clinical improvement, and a long-term IVIG replacement was initiated due to hypogammaglobulinemia. Four months later, the patient presented with severe abdominal pain, fever, pancytopenia, splenomegaly, hyperferritinemia, and markedly elevated soluble IL-2 receptor levels (9,840 IU/mL), consistent with a third episode of EBV-associated HLH (viral load 207,000 viral copies/mL). Treatment was initiated according to the HLH-2014 protocol, including dexamethasone, immunomodulatory IVIG, and rituximab. Despite transient improvement, clinical and laboratory deterioration occurred, prompting escalation with high-dose methylprednisolone pulses, leading to significant clinical improvement. Interestingly, bone marrow biopsy performed before treatment revealed infiltration consistent with HL. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated active disease in the spleen and bone marrow, establishing a stage IVA diagnosis. Chemotherapy with the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) protocol was initiated. After two cycles, interim FDG-PET/CT showed complete metabolic remission (Deauville score 1/2), and treatment continued with four cycles of AVD, according to European Society for Medical Oncology (ESMO) guidelines. Key Messages for Clinical Practice This case illustrates that XLP1 patients remain at lifelong risk for EBV-driven HLH and rare lymphomas, and emphasizes that early recognition, vigilant monitoring, and prompt targeted therapy, including rituximab and tailored chemotherapy, can achieve complete remission, even in this high-risk population.
2025-04-25 | Addition of Thiotepa to Alemtuzumab, Fludarabine, and Melphalan Reduced-Intensity Conditioning Reduces Secondary Graft Failure in Allogeneic HSCT for Inborn Errors of Immunity
Introduction Alemtuzumab, fludarabine, and melphalan reduced-intensity conditioning (RIC) regimen is associated with a high incidence of mixed chimerism and secondary graft failure in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) for inborn errors of immunity (IEI). We hypothesized that addition of thiotepa to this regimen would reduce secondary graft failure without increasing toxicity in children and young adults undergoing allogenic HSCT for IEI. Methods We retrospectively reviewed charts of patients undergoing allogenic HSCT for IEI who received alemtuzumab (starting on day -14), fludarabine (150 mg/m2 or 5 mg/kg over days -8 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg on day -3) containing RIC regimen with the addition of thiotepa (200 mg/m2 on day -2). Mixed chimerism and low-level mixed chimerism were defined as whole blood donor chimerism <95% and <50%, respectively, on two consecutive measures within a 2-week period. Results Thirty-one patients underwent allogeneic HSCT at a median age of 1.7 years (0.3-21 yrs). Patient demographics are outlined in Table 1. All patients engrafted at a median of 12 days (range, 8-17 days). The incidence of mixed chimerism was 0% (0/31), 20% (5/25), and 46% (7/15) upon engraftment at day +100 and one-year post-HSCT, respectively. Incidence of low-level mixed chimerism was 0% (0/25) and 6.6% (1/15) at day +100 and one-year post-HSCT, respectively. Three (9.6%) patients required a secondary intervention (2 CD34 selected boost and 1 second HSCT). Two (6.4%) patients developed sinusoidal obstruction syndrome, and 11 (35%) patients developed thrombotic microangiopathy. Six (19%) patients developed grade I-II skin GVHD, with none developing grade III-IV GVHD. One (3.2%) patient developed limited chronic GVHD. Thirteen of 31 (42%) patients had viral reactivation requiring treatment, with CMV (54%), EBV (54%), and adenovirus (15%) being the most common. Twenty-six (84%) patients are surviving at median follow-up of 10 months (range 2m-4y 2m) post-HSCT. Table 1.Patient demographics (n = 31).Median age at transplant (range)1y 8m (4m-21y 11m)Median Follow up (range)10 m (2m-4y 2m)GenderMale19 (61%)Female12 (39%)DiagnosisHLH19 (61%)sJIA5 (16%)XLP1 (3.2%)XIAP1 (3.2%)LRBA deficiency1 (3.2%)XMEN1 (3.2%)SCID1 (3.2%)Griscelli1 (3.2%)Early onset IBD1 (3.2%)Donor RelationshipRelated21 (68%)Unrelated10 (32%)HLA Match10/1021 (68%)9/106 (19%)7/101 (3%)6/103 (10%)Stem cell sourceBM23 (74%)PBSCs, CD34 selected5 (16%)PBSCs, alpha beta depleted3 (10%)GVHD prophylaxisCSA/MMF11 (35.5%)CSA/MMF/Abatacept10 (32%)CD34 selection5 (16%)Alpha-beta T cell depletion3 (10%)CSA/MMF/PT-Cy2 (6.5%) Conclusion Addition of thiotepa to a RIC regimen containing fludarabine, alemtuzumab, and melphalan reduces secondary graft failure without increasing toxicity in children and young adults undergoing allogenic HSCT for IEI. Longer duration of follow-up is needed to assess durability of donor chimerism.
2024-05-01 | X-Linked Lymphoproliferative Disease Type 2 With Activation of Hemophagocytic Lymphohistiocytosis Secondary to Epstein-Barr Virus Infection
Hemophagocytic lymphohistiocytosis (HLH) is a rare yet potentially life-threatening syndrome. It is best described as uncontrolled immune system activation leading to hemophagocytosis. Our case report aims to present a practical approach, discuss the challenges in the diagnosis and management of HLH, and to shed light on the X-linked lymphoproliferative disease type 2 (XLP-2) gene, STXBP2 gene (as a carrier), and Epstein-Barr virus (EBV) infection in relation to HLH. This is a 2-year-8-month-old Saudi boy, who presented to the emergency department with fever for more than 7 days, not associated with any other major complaints. During the first couple of days of admission, primary results showed hyperferritinemia, low fibrinogen, anemia, high inflammatory markers, high D-dimer, and increasing liver enzymes and triglycerides. The patient fulfilled the diagnostic criteria of HLH on the third day of admission. Further investigations revealed a genetic mutation in XLP-2 gene, STXBP2 gene (as a carrier) and EBV infection causing HLH. HLH-94 protocol was used for management. The patient had an excellent clinical outcome, unexpectedly, by only using dexamethasone, with complete remission and no recurrence up to date. HLH is not frequently encountered in daily practice. However, it can be fatal. This case report describes a unique case of XLP-2, STXBP2 carrier with extreme EBV infection and activation of HLH, who was successfully brought into remission by partial application of HLH-94 protocol and careful clinical and laboratory monitoring. The diagnosis and management of HLH can be challenging. However, a reasonable clinical judgment can improve the outcomes. Int J Clin Pediatr. 2024;13(1):26-33 doi: https://doi.org/10.14740/ijcp525
2024-03-22 | CXCR4: from B-cell development to B cell–mediated diseases
Chemokine receptors are members of the G protein–coupled receptor superfamily. The C-X-C chemokine receptor type 4 (CXCR4), one of the most studied chemokine receptors, is widely expressed in hematopoietic and immune cell populations. It is involved in leukocyte trafficking in lymphoid organs and inflammatory sites through its interaction with its natural ligand CXCL12. CXCR4 assumes a pivotal role in B-cell development, ranging from early progenitors to the differentiation of antibody-secreting cells. This review emphasizes the significance of CXCR4 across the various stages of B-cell development, including central tolerance, and delves into the association between CXCR4 and B cell–mediated disorders, from immunodeficiencies such as WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome to autoimmune diseases such as systemic lupus erythematosus. The potential of CXCR4 as a therapeutic target is discussed, especially through the identification of novel molecules capable of modulating specific pockets of the CXCR4 molecule. These insights provide a basis for innovative therapeutic approaches in the field.
2022-12-15 | Allosteric inhibition of SHP2 rescues functional T-cell abnormalities in SAP deficiency.
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency arising from SH2D1A mutations leading to loss of SLAM-associated protein (SAP). SAP is an intracellular adaptor protein that binds to SLAM family receptors and is expressed in specific lymphoid lineages. In T cells, SAP relays activatory signals from the T-cell receptor but in its absence SH2 containing protein tyrosine phosphase-1 (SHP1), SH2 containing protein tyrosine phosphase-2 (SHP2), and SH2 containing inositol 5'-phosphatase proteins (SHIP) induce T-cell inhibitory signals leading to abnormal T-cell responses. This results in severe clinical manifestations including immune dysregulation, dysgammaglobulinemia, lymphoma, and hemophagocytic lymphohistiocytosis. Current treatment relies on supportive therapies including immunoglobulin replacement and symptom-directed therapy, with hematopoietic stem cell transplant offering the only curative option. As most XLP symptoms are due to defective T-cell function, this study investigated whether inhibition of SHP2 can restore cellular function in the absence of SAP. Healthy donor and XLP patient T cells were activated with anti-CD3/CD28 in T-cell media supplemented with a SHP2 inhibitor (RMC-4550 in vitro for 24 hours) and functional assays were performed to assess follicular TH (TFH) cell function, CD8 cytotoxicity, and sensitivity to restimulation-induced cell death. Additionally, SAP-deficient (SAPy/-) mice were treated with RMC-4550 before T-cell mediated challenge with 4-hydroxy-3-nitrophenylacetly conjugated chicken gammaglobulin and subsequent assessment of humoral immunity analyzing TFH cell population, germinal center formation, and antigen-dependent immunoglobulin secretion. This study shows that the use of RMC-4550 restores T-cell function in XLP patient cells and a SAPy/- model, demonstrating restoration of TFH cell function through immunoglobulin and cytokine secretion analysis alongside rescue of cytotoxicity and restimulation-induced cell death. These data suggest that SHP2 inhibitors could offer a novel and effective targeted treatment approach for patients with XLP.
gene therapies
2025-10-08 | Image 2_X-linked lymphoproliferative disease with initial onset of neurological symptoms: a case and literature review.jpg
X-linked lymphoproliferative syndrome type 1 (XLP-1) is a life-threatening X-linked recessive immunodeficiency classically characterized by susceptibility to Epstein–Barr virus (EBV), hypogammaglobulinemia, and lymphoma. While neurological involvement can occur, it is exceptionally rare as the initial and predominant manifestation. This case report details a novel presentation of XLP-1 in a 4-year-old boy who presented with acute, initial neurological symptoms (sudden fever, headache, and vomiting) in the absence of typical immune dysregulation features. Whole-exome sequencing (WES) identified a hemizygous variant in the SH2D1A gene (c.1A>G, p. Met1Val), predicted as damaging/disease-causing by MutationTaster (probability = 0.993) and PolyPhen-2 (probability = 0.992). Meanwhile, according to the American College of Medical Genetics and Genomics (ACMG) guidelines for variant interpretation, this variant met four evidence criteria (PVS1_Moderate+ +PM2_Moderate+PP3+PP5) and was classified as pathogenic. Structural analysis leveraging the AlphaFold protein structure database demonstrated that this variant disrupts the Kozak consensus sequence and splice site, critically impairing start codon recognition and translation initiation, thereby explaining the loss of functional SLAM-associated protein (SAP) protein expression. This case, along with a focused review of the literature, underscores that XLP-1 rarely presents primarily with neurological symptoms, broadening the clinical phenotype spectrum and emphasizing the need for early genetic evaluation in children with unexplained acute neurological presentations, even in the absence of overt immunodeficiency signs. This finding provides crucial clinical data for a more comprehensive understanding of XLP-1.
2025-09-05 | Severe Oral Lichen Planus Masking a Primary Immunodeficiency: X-Linked Lymphoproliferative Disease Type 1 (XLP-1).
A 14-year-old boy was initially diagnosed with erosive oral lichen planus based on clinical and histopathological findings. However, the atypical clinical course and resistance to immunosuppressive therapy raised suspicion for an autoinflammatory disorder or inborn error of immunity. Genetic testing revealed a pathogenic SH2D1A mutation, confirming X-linked lymphoproliferative disease type 1 (XLP-1) in the absence of Epstein-Barr virus exposure. This case highlights oral mucosal lesions as a potential early, EBV-independent manifestation of XLP-1 and emphasizes the importance of considering monogenic immune disorders in persistent, treatment-refractory mucosal disease.
2025-06-27 | X-linked lymphoproliferative disease type 1: a clinical and genetic update.
X-linked lymphoproliferative disease (XLP), also known as Duncan's disease, is a primary immunodeficiency disorder linked to the X chromosome. In 1998, SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), was identified as the first pathogenic gene associated with XLP. To date, more than 100 mutation sites in this gene have been documented. The disease is associated with infection with Epstein-Barr virus (EBV) and characterized by hemophagocytic lymphohistiocytosis (HLH), hypogammaglobulinemia, and lymphomas. Pathogenesis is intricately associated with cell type-specific SAP-SLAM signaling pathways. Particularly, the immune cell defects involve impaired T cell-B cell interactions, reduced cytotoxicity of Natural Killer (NK) cells, and abnormal development of Natural Killer T (NKT) cells. These factors collectively increase susceptibility to EBV and drive clinical manifestations in XLP type 1 (XLP1) patients. Although establishing a definitive correlation between specific genotypes and clinical phenotypes remains challenging, emerging evidence suggests a potential association. This underscores the critical need for further large-scale studies to elucidate this relationship. Given the current understanding of the pathophysiological mechanisms associated with XLP1, specific treatments to normalize SAP expression and restore immune tolerance in XLP1 patients play an important role. In addition to the necessity for long-term studies to verify the efficacy and safety of hematopoietic stem cell transplantation (HSCT), gene therapies currently under development, along with other emerging treatments, exhibit substantial promise for future clinical applications.
2024-09-23 | Lentiviral vectors for precise expression to treat X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease (XLP1) results from SH2D1A gene mutations affecting the SLAM-associated protein (SAP). A regulated lentiviral vector (LV), XLP-SMART LV, designed to express SAP at therapeutic levels in T, NK, and NKT cells, is crucial for effective gene therapy. We experimentally identified 34 genomic regulatory elements of the SH2D1A gene and designed XLP-SMART LVs to emulate the lineage and stage-specific control of SAP. We screened them for their on-target enhancer activity in T, NK, and NKT cells and their off-target enhancer activity in B cell and myeloid populations. In combination, three enhancer elements increased SAP promoter expression up to 4-fold in on-target populations in vitro. NSG-Tg(Hu-IL15) xenograft studies with XLP-SMART LVs demonstrated up to 7-fold greater expression in on-target cells over a control EFS-LV, with no off-target expression. The XLP-SMART LVs exhibited stage-specific T and NK cell expression in peripheral blood, bone marrow, spleen, and thymic tissues (mimicking expression patterns of SAP). Transduction of XLP1 patient CD8+ T cells or BM CD34+ cells with XLP-SMART LVs restored restimulation-induced cell death and NK cytotoxicity to wild-type levels, respectively. These data demonstrate that it is feasible to create a lineage and stage-specific LV to restore the XLP1 phenotype by gene therapy.
2019-08-02 | Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease.
X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects. CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen-specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. In Sap-deficient mice 20% to 40% engraftment of gene-modified T cells led to significant recovery of germinal center formation and NP-specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1.
cell therapies
2025-10-22 | The neurologic face of X-linked lymphoproliferative syndrome type 1: a systematic review.
X-linked lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity with high mortality rates. Neurological manifestations may be the presenting features and are often fatal; however, their characterization is insufficient, hindering optimal clinical management. The aim of this study is to systematically review the neurological characteristics, outcomes, and survival in XLP1 patients and identify parameters associated with improved prognosis. A PRISMA-guided analysis of PubMed, Web of Science, Scopus, and Embase (up to March 2025) identified studies documenting neurological involvement in genetically verified XLP1 patients. We extracted data on clinical features, neuroimaging findings, therapeutic interventions, and survival. We identified 42 genetically verified XLP1 patients with neurological involvement. Central nervous system (CNS) involvement comprised hemophagocytic lymphohistiocytosis (HLH) in 38.1%, vasculitis in 28.6%, and lymphoma in 19% of them. The development of brain vasculitis several months after Burkitt’s lymphoma was a specific presentation. The median age of neurological onset was 5 years. The predominant presenting symptoms were seizures (47.6%), altered consciousness (35.7%), and headaches (21.4%). Neuroimaging frequently revealed abnormalities in the temporal lobe and basal ganglia, often with hemorrhage and edema. Epstein-Barr virus (EBV) was identified in 54.8% of cases, sometimes limited to brain tissue. CSF analysis frequently showed elevated protein and pleocytosis. SH2D1A mutations were diverse, with Arg55 and Trp64 identified as recurrent hot spots. The overall mortality reached 52.4%, with most deaths occurring within five years of neurological onset. Conventional immunosuppressive and cytotoxic treatments were largely ineffective in changing the disease course. In exploratory analysis, hematopoietic stem cell transplantation (HSCT) did not significantly improve survival in the primary dataset, although sensitivity analysis suggested a possible benefit. Neurological involvement in XLP1 exhibits clinical heterogeneity and carries a high mortality rate. Early recognition and timely HSCT may improve survival, demonstrating the importance of vigilant neurological monitoring in affected individuals. The online version contains supplementary material available at 10.1186/s13023-025-04057-9.
2023-02-28 | Clinical Case of X-Linked Lymphoproliferative Syndrome Burdened with Hemophagocytic Lymphohistiocytosis and Crohn's Disease
Background . X-linked lymphoproliferative (XLP) syndrome is hereditary disease with the incidence of 1-3 per 1 million born boys. This clinical case demonstrates a rare picture of XLP type 2 manifestation without prior Epstein-Barr virus. Clinical case description . Boy D., 15 years old, was admitted to Morozovskaya Children's City Hospital with complaints on fever, abdominal pain, loose stools, weight loss. The past medical history included hemophagocytic syndrome (remission) and acute erythema nodosum. We have performed several studies: abdominal ultrasound (hepatomegaly, dynamic changes in the intestine: parts of the small intestine were enlarged and walls were thickened, mass peristalsis, walls of transverse colon and descending colon are thickened up to 5 mm, mesenteric lymphadenopathy), rectosigmoidoscopy (high-activity ulcerative proctosigmoiditis corresponds to Crohn's disease), biochemical and clinical blood tests (active hemophagocytic syndrome), coagulogram (secondary hypocoagulation), myelogram (no data on hemoblastosis or aplastic condition). Virological blood tests (CMV, EBV, HHV-VI): negative. Laboratory and instrumental tests have revealed recurrence of hemophagocytic syndrome and Crohn's disease. The child was consulted by rheumatologist, hematologist, gastroenterologist, geneticist, neurologist, and clinical pharmacologist. The primary immune deficiency disease was suspected in this patient due to his medical history. Molecular genetic study was performed (deletion including the XIAP gene was revealed) and the diagnosis of primary immune deficiency was verified: X-linked lymphoproliferative syndrome type 2. Thus, allogeneic haematopoietic stem cell transplantation (HSCT) was performed. Conclusion . XLP diagnosis and management require multidisciplinary approach. The early diagnosis is crucial due to the high risk of secondary complications development that can significantly worsen the disease's prognosis. Allogeneic HSCT is the only effective treatment for the disease.
2022-10-29 | From inborn errors of immunity to lymphoma: A hematologist’s point of view
After infections, malignancies, lymphomas especially, are the second most frequent cause of death in patients with inborn errors of immunity. Factors predetermining the appearance and aggressiveness of lymphomas include gene defects, defects of immune surveillance and regulation as well as infections with oncogenic viruses. Aggressive non-Hodgkin lymphomas, mostly diffuse large B-cell and Bukit subtypes are predominant in deoxyribonucleic acid repair defects, while Hodgkin lymphoma becomes equally present in patients with defects of immune regulation. Marginal zone and mucosa-associated lymphoid tissue lymphomas, appear to be frequent in defects of antibody production, especially in patients with common variable immune deficiency. The prevalence of Epstein-Barr virus may vary within entities, but there is no entity without at least a few cases of lymphoma and Epstein-Barr virus co-infection. Standard treatment of lymphomas associated with deoxyribonucleic acid repair defects and severe combined deficiencies, is stem cell transplantation. Lymphomas in inborn errors of immunity with a less severe clinical presentation, should be treated with immunochemotherapy and monoclonal antibodies (Brentuximab, Rituximab) wherever feasible. There is no data about the usefulness of checkpoint inhibitors, bi-specific antibodies and T-cells with chimeric antigen receptor. Allogeneic stem cell transplantation represents a major indication for treatment of relapse/refractory lymphomas in any inborn error of immunity. Potential benefit of therapy with Chimeric antigen receptor Natural-killer cells in lymphomas associated with inborn errors of immunity, remains to be seen in future studies.
2022-04-18 | Preemptive hematopoietic cell transplantation for asymptomatic patients with X-linked lymphoproliferative syndrome type 1.
Few reports have examined whether prophylactic allogeneic hematopoietic cell transplantation (HCT) for X-linked lymphoproliferative syndrome type 1 (XLP1) improves the prognosis. We compared the prognosis of symptomatic probands and affected siblings in the same family. Twenty-two cases (10 probands and 12 affected siblings) in Japan, the United Kingdom, and the United States were analyzed. The overall survival (OS) rate at 5 years after diagnosis was 70.0% in probands and 91.7% in affected siblings (p = 0.0789). The prognosis of patients who developed symptoms of XLP1 before HCT and those who did not was also compared. The 5-year probability of OS from the time of diagnosis in asymptomatic patients (100%) was significantly better than that in symptomatic patients (66.7%). These results suggested that early HCT as soon as the diagnosis is made improves the prognosis in asymptomatic XLP1 patients.
2022-01-05 | Two Clonally Distinct B-Cell Lymphomas Reveal the Diagnosis of XLP1 in a Male Child and His Asymptomatic Male Relatives: Case Report and Review of the Literature.
X-linked lymphoproliferative disease type 1 (XLP1) is a primary immunodeficiency disorder caused by pathogenic variants in the SH2D1A gene (SH2 domain containing protein 1A). Patients with XLP1 may present acutely with fulminant infectious mononucleosis, hemophagocytic lymphohistiocytosis, and/or B-cell non-Hodgkin lymphoma (B-NHL). We report a boy who developed 2 clonally distinct B-NHL 4 years apart and was found to have previously unrecognized XLP1. The report highlights the importance of clonal analysis and XLP1 testing in males with presumed late recurrences of B-NHL, and the role of allogeneic stem cell transplant (allo-SCT) in XLP1 patients and their affected male relatives.
antibodies
2025-11-03 | Hemophagocytic lymphohistiocytosis of the ocular adnexal mimicking orbital cellulitis in a patient with unknown X-linked lymphoproliferative syndrome type 1 (XLP1): Case report and literature review.
A 5-year-old boy presented with severe acute bilateral periorbital edema. Initial misdiagnosis was made as preseptal orbital cellulitis, and he failed to respond to conventional antibiotic therapy. Magnetic resonance imaging revealed thickening of the anterior orbital adipose tissue bilaterally, with hyperintensity on T2-weighted imaging. The biopsy unveiled lymphoma-associated hemophagocytic syndrome, specifically Epstein-Barr virus related. The patient was administered rituximab, resulting in a significant amelioration. A family history, coupled with genetic investigation, ultimately led to the diagnosis of X-linked lymphoproliferative syndrome type 1 due to a large deletion of exons 2-4 of *SH2D. Reported ocular manifestation of XLP1 includes retinal hemorrhages, disc edema, acute posterior multifocal placoid pigment epitheliopathy, and macular edema. No ocular adnexal involvement has been previously reported. This case documents a case of XLP1 syndrome affecting the ocular adnexa and emphasizes the critical need to consider underlying immunodeficiencies in patients who do not respond to conventional therapies.
2025-04-25 | Insights into EBV Infection in an Adult with X-Linked Lymphoproliferative Syndrome
Introduction X-linked lymphoproliferative disease (XLP) is a rare inborn error of immunity (IEI) characterized by increased susceptibility to Epstein–Barr Virus (EBV) and other features of immune dysregulation. We present a case of XLP1, diagnosed in a 37-year-old male with EBV viremia treated with nivolumab. Case The proband was diagnosed with common variable immunodeficiency (CVID) and started on IVIG at age 8. Infections were recurrent pneumonias and an episode of septic hip arthritis. He remained infection free over the next 3 decades until presenting with Evans syndrome at age 37, which was initially treated with prednisone. Shortly after, his course was complicated with hepatic and brain abscesses and liver decompensation. Thus, he was referred to our service for workup. Genetic testing revealed the diagnosis of XLP1 (SH2D1A c.138-2A>G). He was found to have EBV viremia, and a liver biopsy suggested EBV hepatitis. He was not a liver transplant candidate due to concern of sepsis given his immunosuppression and IEI. Hematopoietic stem cell transplant (HSCT) was not offered due to high risk of mortality. Despite treatment with rituximab, his repeat EBV titers continued to rise. Virus-specific T cell therapy was pursued; however, the patient was clinically too unstable to be transferred for treatment to the United States from Canada. He was given one nivolumab dose, significantly reducing his viremia. He ultimately succumbed to sepsis and respiratory failure. EBV is the leading cause of mortality in patients with XLP who forego HSCT. Rituximab has been well-documented in the treatment of EBV. We present a patient with an EBV susceptibility syndrome and progressive viremia, who responded well to one dose of nivolumab which significantly reduced his EBV viral load. Despite limited literature, nivolumab may play a significant role in the treatment of certain EBV-associated conditions, particularly in patients with IEIs. In conclusion, nivolumab should be considered for any patient with an overwhelming EBV infection. Severe EBV-induced disease is an unexpected finding in an individual with CVID and warrants genetic testing to exclude other primary immunodeficiencies. Treatment options for EBV susceptibility syndromes need further exploration and accessibility.
2024-04-03 | Case report: EBV-related eye orbits and sinuses lymphohistiocytic infiltration responsive to rituximab in a patient with X lymphoproliferative syndrome type 1
Background and aims X lymphoproliferative syndrome type 1 (XLP1) is a rare inborn error of immunity due to mutations of SH2D1A , encoding for slam-associated protein (SAP). The clinical phenotype includes severe mononucleosis, hemophagocytic lymphohistiocytosis (HLH), and B-cell lymphomas. Methods We report the case of a child affected with XLP1 who presented with an incomplete HLH, triggered by Epstein–Barr virus (EBV) and treated with rituximab, involving orbits and paranasal sinuses. Results The lesion was indistinguishable from lymphoma, complicating diagnosis and treatment. In addition, considering the high incidence of lymphoma in patients with XLP1, histology helped define its nature, driving therapeutic choices. Conclusion We described an unusual presentation of incomplete HLH in a patient affected with XLP1: an EBV-driven infiltration of the orbits and paranasal sinuses. This led us to a challenging differential diagnosis of lymphoma-associated hemophagocytic syndrome, which can be frequently observed in patients with XLP1. Considering the extremely poor prognosis of this clinical finding, we sought for a prompt diagnosis and managed to obtain it and to immediately establish the right treatment on the basis of the pathological finding.
2023-09-01 | X‐linked lymphoproliferative syndrome associated with Epstein–Barr virus encephalitis and lymphoproliferative disorder
When treating patients with EBV encephalitis, the possibility of XLP should be considered. Once the diagnosis of XLP is made, aggressive treatment such as rituximab, and other immunosuppressive agents are desired for rapid transition to HSCT.
2022-08-23 | Fatal X-linked lymphoproliferative disease type 1-associated limbic encephalitis with positive anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody.
X-linked lymphoproliferative disease type 1 (XLP1) is a rare monogenic immune dysregulation disorder caused by a deficiency of a signaling lymphocyte activation molecule-associated protein (SAP). While many patients with XLP1 present with fatal hemophagocytic lymphohistiocytosis upon Epstein Barr virus (EBV) infection, a small fraction present with limbic encephalitis in the absence of EBV infection. It is poorly understood why SAP deficiency may cause limbic encephalitis in XLP1. A 12-year-old boy presented with seizures, changes in personality, memory loss, and cognitive deficits during treatment for interstitial pneumonia. A diagnosis of limbic encephalitis was made. Despite treatment against CD8+ T cell-mediated autoimmunity with intravenous methylprednisolone, dexamethasone, intravenous immunoglobulin, plasma exchange, cyclosporine, weekly etoposide, mycophenolate mofetil, and adalimumab, encephalitis progressed until the patient died after one month of treatment intitiation. Post-mortem genetic testing revealed a de novo SH2D1A truncating mutation. Tests for EBV infection were negative. Initial spinal fluid revealed markedly elevated protein levels, mild pleocytosis, and elevation of two chemokines (C-X-C motif chemokine ligand [CXCL] 10 and CXCL 13). Moreover, initial spinal fluid was tested positive for anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) autoantibody. In XLP1-associated limbic encephalitis, anti-AMPAR autoantibody production by the dysregulated immune system due to SAP deficiency might be a pathogenic mechanism of central nervous system manifestations. In addition to the standard treatment for XLP1, targeted treatment against B-cell-mediated immunity might be indicated for patients with XLP1-associated limbic encephalitis.
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