X-linked Lymphoproliferative Disease Research Articles

Hematological manifestations of X-linked lymphoproliferative disease

Zespół limfoproliferacyjny sprzężony z chromosomem X (XLP) to rzadka choroba genetyczna występująca głównie u chłopców. Istnieją dwa rodzaje choroby, każdy o innej charakterystyce klinicznej i genetycznej. XLP1 jest spowodowane mutacją w genie SH2D1A, a XLP2 mutacją w genie XIAP/BIRC. Wady genetyczne prowadzą do dysfunkcji układu odpornościowego. Objawy kliniczne mogą wykazywać różnice, nawet wśród członków rodziny, którzy są nosicielami tej samej mutacji. Manifestacja jest zespołem zaburzeń hematologicznych: choroba objawia się najczęściej limfohistiocytozą hemofagocytarną, dysgammaglobulinemią, piorunującą mononukleozą zakaźną, splenomegalią, występowaniem chłoniaków z komórek B zlokalizowanych w pobliżu zastawki krętniczo-kątniczej i zapaleniem jelita grubego. Diagnostyka różnicowa powinna przede wszystkim uwzględniać wrodzone niedobory odporności. XLP jest chorobą śmiertelną, ale wraz z rozwojem nowych opcji leczenia, oczekiwana długość życia pacjentów znacznie się wydłużyła. Obecnie jedynym ostatecznym sposobem leczenia jest wczesne allogeniczne przeszczepienie krwiotwórczych komórek macierzystych. Pojawienie się nasilonych objawów przed przeszczepieniem zmniejsza szanse pacjenta na sukces terapeutyczny. W związku z tym bardzo ważne jest postawienie wczesnej diagnozy. Nowe terapie, które obejmują hamowanie enzymów, terapię genową i edycję genów budzą nadzieje klinicystów. Pacjentom i ich rodzinom należy zapewnić poradnictwo genetyczne oraz możliwość wczesnej diagnostyki molekularnej.

Patients with XLP type 1 have variable numbers of NKT cells.

X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency that usually presents in early childhood. Patients with XLP1 have been reported to have absent NKT cells, and it has been suggested that this can be diagnostic for the disorder. Whilst NKT frequency in adults is variable, little is known about their frequency in children. Therefore, we established a paediatric reference range for these cells. In contrast to previous reports, in our cohort of XLP1 patients, NKT cell numbers were found to be variable, and we would advise against using the finding of NKT cells to exclude a diagnosis of XLP1.

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.

Simple Evaluation of Clinical Situation and Subtypes of Pediatric Hemophagocytic Lymphohistiocytosis by Cytokine Patterns.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal disease caused by immune dysregulation. Early initiation of treatment is imperative for saving lives. However, a laboratory approach that could be used to quickly evaluate the HLH subtype and clinical situation is lacking. Our previous studies indicated that cytokines such as interferon (IFN)-γ and interleukin (IL)-10 were helpful for the early diagnosis of HLH and were associated with disease severity. The purpose of this study is to clarify the different cytokine patterns of various subtypes of pediatric HLH and to investigate the role of cytokines in a simple evaluation of disease feature.Patients and MethodsWe enrolled 256 pediatric patients with newly diagnosed HLH. The clinical features and laboratory findings were collected and compared among different subtypes of HLH. A model integrating cytokines was established to stratify HLH patients into different clinical groups.ResultsTwenty-seven patients were diagnosed with primary HLH (pHLH), 179 with EBV-HLH, and 50 with other causes. The IL-6, IL-10, and IFN-γ levels and the ratios of IL-10 to IFN-γ were different among EBV-HLH, other infection-associated HLH, malignancy-associated HLH, familial HLH, and X-linked lymphoproliferative disease. Patients with the ratio of IL-10 to IFN-γ >1.33 and the concentration of IFN-γ ≤225 pg/ml were considered to have pHLH, with a sensitivity of 73% and a specificity of 84%. A four-quadrant model based on the two cutoff values was established to stratify the patients into different clinical situations. The HLH subtypes, cytokine levels, treatment regimens, treatment response, and outcomes were different among the four quadrants, with the 8-week mortality from 2.9 ± 2.9% to 21.4 ± 5.5% and the 5-year overall survival from 93.9 ± 4.2% to 52.6 ± 7.1%.ConclusionsDifferent subtypes of HLH present distinct cytokine patterns. IFN-γ and the ratio of IL-10 to IFN-γ are helpful tools to differentiate HLH subtypes. A four-quadrant model based on these two parameters is a useful tool for a simple evaluation of the HLH situation.

Identification of Germline Non-coding Deletions in XIAP Gene Causing XIAP Deficiency Reveals a Key Promoter Sequence

X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants inXIAPincluding missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons ofXIAPwas identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression. Targeted next-generation sequencing (NGS) of the entire locus ofXIAPwas performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells. NGS ofXIAPidentified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839bp that encompassed the first non-coding exon ofXIAPand contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression. These results identify a key promoter sequence contained in the first non-coding exon ofXIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.

XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting innate immune responses of Paneth and dendritic cells.

Deficiency in X-linked inhibitor of apoptosis protein (XIAP) is the cause for X-linked lymphoproliferative syndrome 2 (XLP2). About one-third of these patients suffer from severe and therapy-refractory inflammatory bowel disease (IBD), but the exact cause of this pathogenesis remains undefined. Here, we used XIAP-deficient mice to characterize the mechanisms underlying intestinal inflammation. In Xiap−/− mice, we observed spontaneous terminal ileitis and microbial dysbiosis characterized by a reduction of Clostridia species. We showed that in inflamed mice, both TNF receptor 1 and 2 (TNFR1/2) cooperated in promoting ileitis by targeting TLR5-expressing Paneth cells (PCs) or dendritic cells (DCs). Using intestinal organoids and in vivo modeling, we demonstrated that TLR5 signaling triggered TNF production, which induced PC dysfunction mediated by TNFR1. TNFR2 acted upon lamina propria immune cells. scRNA-seq identified a DC population expressing TLR5, in which Tnfr2 expression was also elevated. Thus, the combined activity of TLR5 and TNFR2 signaling may be responsible for DC loss in lamina propria of Xiap−/− mice. Consequently, both Tnfr1−/−Xiap−/− and Tnfr2−/−Xiap−/− mice were rescued from dysbiosis and intestinal inflammation. Furthermore, RNA-seq of ileal crypts revealed that in inflamed Xiap−/− mice, TLR5 signaling was abrogated, linking aberrant TNF responses with the development of a dysbiosis. Evidence for TNFR2 signaling driving intestinal inflammation was detected in XLP2 patient samples. Together, these data point toward a key role of XIAP in mediating resilience of TLR5-expressing PCs and intestinal DCs, allowing them to maintain tissue integrity and microbiota homeostasis.

Bispecific Antibody Designed for Targeted NK Cell Activation and Functional Assessment for Biomedical Applications.

Natural killer (NK) cells serve as key innate effectors and their activity has been considered a prognostic biomarker in diverse human diseases. Currently, NK cell functional assays have several problems primarily related to adequate preparation, labeling, or treatment of target cells, which are cumbersome and often hamper consistent sensitivity for NK cells. Here, bispecific antibodies (BsAb's) targeting NKG2D and 2B4 receptors, whose combination mounts selective cytotoxicity and IFN-γ production of NK cells, are developed as acellular, consistent, and easy-to-use strategies for assessing NK cell functions. These NK cell activator BsAb's (NKABs) are constructed in symmetric dual bivalent formats with different interdomain spacings [immunoglobulin G (IgG)-single-chain variable fragment (scFv) and dual-variable domain (DVD)-Ig] and kappa constant (Cκ)-scFv format linking two scFv's with a Cκ domain. These NKABs are specific and superior to a combination of monospecific antibodies for NK cell activation. NKAB elicits both direct cytotoxicity and IFN-γ production via integration of NKG2D and 2B4 signals. Moreover, stimulation with NKAB IgG-scFv and Cκ-scFv reveals defective NK cell functions in X-linked lymphoproliferative disease involving 2B4 dysfunction in NK cells and multiple myeloma in peripheral blood mononuclear cells and whole blood, respectively. Hence, this work provides a proof of concept that NKAB facilitates the reliable and comprehensive measurement of NK cell function in clinical settings for diagnostic and prognostic purposes.

Allogeneic Stem Cell Transplantation for the Treatment of Lymphoproliferative Disorders in Patients Affected By Primary Immunodeficiencies: The UK Experience

▪Malignancies represent a significant morbidity for patients (pts) affected by primary immunodeficiency (PID). 4-25% of pts with PID will develop a malignancy during the course of their life, lymphoproliferative disorders being the most common. Dysfunctional T-cell surveillance, particularly against EBV, and impaired DNA repair mechanisms lie at the basis of this susceptibility. Malignancies in PID pts are difficult to treat as these pts often harbor co-morbidities that increase the risk of treatment-related toxicity. Allogeneic stem cell transplantation (SCT) offers a treatment for both PID and LPD. Data on the outcome of pts referred to SCT for LPD in PID are scant, as PID are rare and sometimes under diagnosed.We retrospectively collected data on pts 0-18 years referred to SCT for LPD in PID in the 12 pediatric SCT centres in the UK from 2000 to 2015. Centralized review for histopathology specimens and radiological imaging was performed to confirm the LPD diagnosis and the disease staging/remission status at SCT. Ethical approval was obtained.40 patients affected by 13 different PIDs were identified, X-linked lymphoproliferative disease being the most common (15% of the pts).Median age at LPD diagnosis was 6.1 years (range 0.2-17.2). Pts were diagnosed with a B-cell lymphoma (60%), Hodgkin lymphoma (15%), polymorphic LPD (10%), plasmacytic hyperplasia (7%), T-cell lymphoma (5%) or atypical lymphoid proliferation (3%). 83% of the pts presented with stage III/IV disease, 4% had CNS involvement. LPD proved EBER positive in 66% of the tested samples. Pts received a median of 2 lines of chemo/immunotherapy to treat LPD, which proved resistant to front line treatment in 64% of the pts. 7 pts were referred for SCT but did not receive one due to disease progression (3), donor unavailability (1) or medical decision (3). Among the non-transplanted pts, 1 died from sepsis during chemotherapy, 4 died from disease progression; the OS of this group is 28% at a median follow up of 10 months from LPD diagnosis. For the 33 pts who underwent SCT, median age at SCT was 8.4 yrs (range 0.6-17.7). 58% of the pts had 1 or more comorbidities at SCT (chronic lung disease being most common). Of these, 67% of the pts receiving SCT were in complete remission (CR), 24% in partial remission, and 10% had active disease when starting their conditioning regimen.7 different types of conditioning regime were used, as per participating center local policies. In 94% of the cases a reduced intensity conditioning (RIC) was used. 74% of treated pts received in vivo T cell depletion with Alemtuzumab (71%) or Anti-Thymocyte Globulin (3%). 27% of the pts received the graft from a matched related, 39% matched unrelated and 33% mismatched donor. Bone marrow and peripheral blood were the most common sources of stem cells (46% and 42% of the cases, respectively).All pts achieved neutrophil engraftment and secondary graft loss was experienced by 2 pts (6%). 4 pts (12%) died from SCT related toxicity (3 infections, 1 pulmonary VOD/hemorrhage). Acute GVHD grade I-IV developed in 42% of the pts. LPD recurred in 2 cases (1 after secondary graft loss) and was successfully treated with surgery/chemotherapy. With a median follow up of 48 months, 88.0% patients are alive, in CR post SCT. 76% of the evaluable patients exhibited a full donor engraftment at the latest follow up.Disease stage, histology, underlying PID and remission status at SCT did not impact on the patients´ outcomes. Overall survival was significantly higher in SCT recipients as compared to patients who did not receive SCT (88 vs 28%, p= 0.03). Even among the 3 pts who underwent SCT without achieving LPD remission, OS was 67%, thus underlying that restoring competent immunity might play a role in this context, allowing for LPD control post SCT via the newly grafted T-cells.This cohort of pts is the largest described of its kind. We conclude that SCT with RIC is safe and efficacious for pts affected by LPD in PID. While larger cohorts of pts are required to confirm these data, our study suggests that remission status at SCT plays a partial role in LPD control. As a consequence, limited pre-SCT chemotherapy might be required and SCT indication might be plausible for pts not achieving CR. DisclosuresLucchini:Alexion: Membership on an entity's Board of Directors or advisory committees.

Haemophagocytic lymphohistiocytosis and Epstein-Barr virus: a complex relationship with diverse origins, expression and outcomes.

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non-familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X-linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non-neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders and lymphomas can cause neoplasia-associated HLH. The present review will discern between EBV-associated familial and non-familial HLH and highlight diagnostic and therapeutic considerations. Non-familial EBV-associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non-neoplastic EBV-HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV-positive T-cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV-related complications is desperately needed to improve survival for patients with neoplasia-associated HLH.

Epstein-Barr virus (EBV) hyperimmune globulin isolated from donors with high gp350 antibody titers protect humanized mice from challenge with EBV

Primary infection with Epstein-Barr virus (EBV) is associated with post-transplant lymphoproliferative disease and severe disease in patients with X-linked lymphoproliferative disease; no therapies are approved to prevent EBV infection in these patients. Hyperimmune globulin has been used to prevent some virus infections in immunocompromised persons. Here, we identified plasma donors with high titers of EBV gp350 and EBV B cell neutralizing antibodies. Pooled IgG isolated from these donors was compared to intravenous immunoglobulin (IVIG) for its ability to reduce viral load in the blood in humanized mice challenged with EBV. Mice that received EBV hyperimmune globulin had significantly reduced EBV DNA copy numbers compared to animals that received saline control; however, while animals that received EBV hyperimmune globulin had lower EBV DNA copies than those that received IVIG, the difference was not significant. Thus, while EBV hyperimmune globulin reduced viral load compared to IVIG, the effect was modest.

Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1.

Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8+ cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8+ expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach.

Infection-induced inflammation from specific inborn errors of immunity to COVID-19.

Inborn errors of immunity (IEIs) are a group of genetically defined disorders leading to defective immunity. Some IEIs have been linked to mutations of immune receptors or signaling molecules, resulting in defective signaling of respective cascades essential for combating specific pathogens. However, it remains incompletely understood why in selected IEIs, such as X‐linked lymphoproliferative syndrome type 2 (XLP‐2), hypo‐immune response to specific pathogens results in persistent inflammation. Moreover, mechanisms underlying the generation of anticytokine autoantibodies are mostly unknown. Recently, IEIs have been associated with coronavirus disease 2019 (COVID‐19), with a small proportion of patients that contract severe COVID‐19 displaying loss‐of‐function mutations in genes associated with type I interferons (IFNs). Moreover, approximately 10% of patients with severe COVID‐19 possess anti‐type I IFN‐neutralizing autoantibodies. Apart from IEIs that impair immune responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), SARS‐CoV‐2 encodes several proteins that suppress early type I IFN production. One primary consequence of the lack of type I IFNs during early SARS‐CoV‐2 infection is the increased inflammation associated with COVID‐19. In XLP‐2, resolution of inflammation rescued experimental subjects from infection‐induced mortality. Recent studies also indicate that targeting inflammation could alleviate COVID‐19. In this review, we discuss infection‐induced inflammation in IEIs, using XLP‐2 and COVID‐19 as examples. We suggest that resolving inflammation may represent an effective therapeutic approach to these diseases.

Successful Salvage Haploidentical Bone Marrow Transplantation in a Child With Hemophagocytic Lymphohistiocytosis, When the Previously Matched Unrelated Donor Tested Positive for SARS-CoV-2 on the Day of Stem Cells Collection

The coronavirus disease 2019 pandemic has made us adjust our standards and cope with unpredictable circumstances affecting the whole world, including the medical field.A 2-year-old boy diagnosed with X-linked lymphoproliferative disease type 2 with concomitant positive polymerase chain reaction test for Epstein-Barr virus–DNA was admitted to our transplant ward. His treatment scheme had to be modified at the last moment because of a donor disqualification due to a positive polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 just before the apheresis. We decided to perform salvage haploidentical bone marrow transplant from the patient's mother because it was the only possible option. Now, in a 5-month observation period after the hematopoietic stem cell transplantation, our patient is in good general condition. His case convinced us to redirect our approach to transplant procedure preparation. Following the European Group of Blood and Marrow Transplantation recommendations, we use cryopreserved apheresis materials to ensure the availability of stem cell products before the start of a conditioning regimen.

Cerebral vasculitis in X-linked lymphoproliferative disease in a Chinese patient

Cerebral vasculitis in X-linked lymphoproliferative disease in a Chinese patient

Macrophage Activation Syndrome - An Unusual Complication Of SLE

Macrophage Activation Syndrome (MAS) is a rare and potentially fatal condition that can complicate many autoimmune diseases. It is a type of Hemophagocytic Lymphohistiocytosis (HLH). HLH is a potentially fatal disease of normal but overactive histiocytes and lymphocytes commonly occurring in infancy but can occur in all age groups. There are two types of HLH: Familial and acquired. Familial HLH is an autosomal recessive disorder and accounts for 25% of the cases. Acquired type is secondary to drugs, malignancies, rheumatological disorders. There are five subtypes of inherited HLH: familial HLH and types 1-5. HLH may result from an inappropriate immune response to a viral illness like EBV. It may be due to X-linked Lymphoproliferative Disease (XLP) caused by a mutation in SH2D1A or XIAP gene. Usually, MAS term is used for HLH secondary to rheumatological disorders that occur mostly in individuals with Systemic Juvenile Idiopathic Arthritis (SJIA) and those with adult-onset Still disease. The condition is thought to be caused due to excessive activation and expansion of T lymphocytes and macrophage histiocytes that show hemophagocytic activity. The expansion of these cells leads to a massive systemic inflammatory response associated with three cardinal features: cytopenias, liver dysfunction, and coagulopathy, resembling Disseminated Intravascular Coagulation (DIC). MAS incidence in SLE patients is estimated to be 0.9% - 4.6%, and it is widely under recognized and underreported. In this report, we enumerate one such case with their clinical presentation, evaluation, and management.

Verification of X-linked lymphoproliferative syndrome type 1 and 2 using a flow cytometry method

Х-linked lymphoproliferative syndrome (XLP) is a life-threatening primary immunodeficiency, characterized by hemophagocytic lymphohistiocytosis, lymphoproliferation and hypogammaglobulinemia. The most frequent forms of XLP – XLP1 and XLP2 – are caused by mutations of the SH2D1A and BIRС4/XIAP genes, coding for SAP and XIAP proteins, respectively. Early diagnosis is important as it allows to prevent severe complications by introducing specific therapy and proceed to hematopoietic stem cell transplantation. Here we describe validation of precise and fast flow cytometry-based method of XLP1 and XLP2 laboratory diagnostics. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. 89 patients from 2 months to 18 years of age seen at our Center from July 2016 to February 2020 with symptoms suspicious of XLP were included in the study. Decrease of SAP intracellular expression was found in 9 patients, and XIAP – in 10 patients. In all of them XLP diagnosis was confirmed by detection of SH2D1A or XIAP mutations, respectively. Female mutations carries from the families of these patients demonstrated abnormal expression of respective proteins. Analysis of the data allowed to calculated the optimized cut-off numbers for the SAP and XIAP expression, which was 50% and 80% in T lymphocytes (respectively) and 45% и 75% in NK lymphocytes (respectively). Specificity and sensitivity of the method was 100% for both proteins. Therefore the method of assessment of SAP and XIAP intracellular expression via flow cytometry allows fast and precise diagnostics of XLP1 and XLP2.

Immune dysregulation symptoms as a rare manifestation of X-linked lymphoproliferative syndrome type 1

X-linked lymphoproliferative syndrome type 1 (XLP1) is a primary immunodeficiency, the most dramatic manifestations of which are hemophagocytic lymphohistiocytosis (usually associated with Epstein-Barr virus), lymphoma and dysgammaglobulinemia. Immune symptoms like vasculitis, aplastic anemia and others are extremely rare. Specialists awareness and suspicion regarding such complications of XLP1 facilitate correct diagnosis and early curative treatment - hematopoietic stem cell transplantation (HSCT). Here we present two clinical cases of XLP1 with immune dysregulation symptoms where one patient underwent successful HSCT. In each case, the parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Correlation of mutations of the SH2D1A gene and Epstein-Barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease

AbstractThe purposes of this study were to determine the frequency of mutations in SH2D1A in X-linked lymphoproliferative disease (XLP) and the role of SH2D1A mutations and Epstein-Barr virus (EBV) infection in determining the phenotype and outcome of patients with XLP. Analysis of 35 families from the XLP Registry revealed 28 different mutations in 34 families—large genomic deletions (n = 3), small intragenic deletions (n = 10), splice-site (n = 3), nonsense (n = 3), and missense (n = 9) mutations. No mutations were found in 25 males, so-called sporadic XLP (males with an XLP phenotype after EBV infection but no family history of XLP) or in 9 patients with chronic active EBV syndrome. Of 304 symptomatic males in the XLP Registry, 38 had no evidence of EBV infection at first clinical manifestation. When fulminant infectious mononucleosis (FIM) was excluded, there was no statistical difference in the frequency of EBV infectivity in the other XLP phenotypes. Furthermore, there was no difference at age of first clinical manifestation between EBV+ and EBV−males or in survival when patients with FIM were excluded. In conclusion, it was found that mutations in the SH2D1A gene are responsible for XLP but that there is no correlation between genotype and phenotype or outcome. It was also found that though EBV infection often results in FIM, it is unnecessary for the expression of other manifestations of XLP, and it correlates poorly with outcome. These results suggest that unidentified factors, either environmental or genetic (eg, modifier genes), contribute to the pathogenesis of XLP.

Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell–directed therapy

AbstractX-linked lymphoproliferative disease (XLP) is a congenital immunodeficiency that is characterized by an abnormal immune response to primary Epstein-Barr virus (EBV) infection. After EBV exposure, affected patients often develop fulminant infectious mononucleosis (FIM), a life-threatening condition marked by the uncontrolled expansion and activation of T and B lymphocytes and macrophages. We hypothesized that the rapid elimination of B cells immediately following EBV exposure might reduce the severity of primary EBV infection in patients with XLP. To test this possibility, we administered the anti-CD20 antibody rituximab to 2 patients who presented with acute infection. Following treatment, both patients exhibited a complete resolution of symptoms and no longer demonstrated detectable EBV DNA within circulating lymphocytes. Moreover, neither patient has developed FIM or lymphoma in more than 2 years of follow-up. These data suggest that the pre-emptive use of B-cell–directed therapy may reduce the morbidity and mortality of primary EBV infection in XLP-affected individuals.

Recurrent lymphadenitis in a female XIAP/BIRC4 mutation carrier with normal lyonization

Deficiency of X-linked inhibitor of apoptosis (XIAP) caused by mutations in XIAP (also known as BIRC4) is a cause of X-linked lymphoproliferative disease,1 characterized by Epstein Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis and hypogammaglobulinemia. Patients with XIAP deficiency also suffer from increased risk of inflammatory conditions such as inflammatory bowel disease (IBD), liver disease, uveitis, erythema nodosum, and arthritis.2-4 Here, we describe a female carrier of an incidentally found pathogenic XIAP mutation with normal lyonization, and her asymptomatic brother.