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The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor

The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term... Hindawi Case Reports in Immunology Volume 2020, Article ID 8841571, 9 pages https://doi.org/10.1155/2020/8841571 Case Report The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor 1 2 3 1 4 Yike Jiang , Mihail Firan, Sarada L. Nandiwada, Anaid Reyes, Rebecca A. Marsh, 1 3 Tiphanie P. Vogel, and Joud Hajjar Texas Children’s Hospital and Baylor College of Medicine, Department of Pediatrics, Section of Rheumatology, Houston, TX, USA Texas Children’s Hospital and Baylor College of Medicine, Department of Pathology and Immunology, Houston, TX, USA Texas Children’s Hospital and Baylor College of Medicine, Department of Pediatrics, Section of Immunology, Allergy and Retrovirology, Houston, TX, USA Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Department of Pediatrics, Section of Bone Marrow Transplantation and Immune Deficiency, Cincinnati, OH, USA Correspondence should be addressed to Joud Hajjar; joud.hajjar@bcm.edu Received 27 June 2020; Revised 31 July 2020; Accepted 12 August 2020; Published 27 August 2020 Academic Editor: Claudio Pignata Copyright © 2020 Yike Jiang et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency characterized by EBV-triggered immune dysregulation, lymphoproliferation, dysgammaglobulinemia, and lymphoma. Early childhood mortality from overwhelming inflammation is expected in most patients. (e only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCTon an asymptomatic patient remains debatable. (is uncertainty arises because the natural history of XLP1 patients without transplantation is not clear. In this case report, we present the natural history of XLP1 in a 43-year-old male patient who did not receive HSCT. We also review the literature on untransplanted XLP1 patients who lived into mid-adulthood. Despite surviving childhood presentations that are typically fatal, we found that these rare patients remain susceptible to manifestations of XLP1 decades later. phosphorylation of the SLAM receptor and recruitment of 1. Introduction downstream signaling molecules, triggering immune cell X-linked lymphoproliferative disease (XLP1) is a primary activation. When SAP is absent in XLP1, these tyrosines on immunodeficiency characterized by severe immune dysre- SLAM bind to strong inhibitory molecules that abrogate gulation triggered by viral infection (commonly EBV), downstream signaling and activation [3]. (e molecular hypogammaglobulinemia, and lymphoma. (is disease is imbalance in SAP deficiency impairs T and NK cell rare with an estimated incidence of 1–3 in 1 ×10 males [1], a function and abolishes NKTdevelopment. Mechanistically, likely underestimate due to the significant risk of early diminished T cell help in germinal centers, compromised childhood death. immunosurveillance, reduced cytotoxicity, and impaired XLP1 is caused by a deficiency in signaling lymphocyte T cell apoptosis leads to dysgammaglobulinemia, lym- activation molecule- (SLAM-) associated protein (SAP). phomas, fulminant infectious mononucleosis, and hemo- SLAM family members are signaling receptors broadly phagocytic lymphohistiocytosis (HLH)—the classic expressed on hematopoietic cells. SAP binds to the in- features of XLP1 [3]. tracellular domain of SLAM proteins, serving as a mo- Diagnosis of XLP1 relies on genetic testing for mutations lecular switch that toggles between cellular activation and in SH2D1A, but rapid immunologic testing is often critical at inhibition [2]. Normally, SAP promotes tyrosine the time of presentation. (is includes the absence of SAP 2 Case Reports in Immunology At age 43, he developed sudden vision change, protein expression by flow cytometry, reduced ex vivo NK cell killing, and the absence of NKT cells [4–7]. headache, right-sided weakness, and seizure. MRI of the brain revealed bilateral areas of acute infarction Since the disease’s discovery in 1975 [8], the only cu- rative therapy for XLP1 is hematopoietic stem cell transplant (Figure 2(b)).Additional evaluation failed to identify a (HSCT). First successfully performed for XLP1 in 1993 [9], primary thrombus. Infectious evaluation was negative for HSCT has since significantly improved overall survival [10]. acute infections such as EBV, VZV, CMV, HHV6, and However, there are rare XLP1 patients who remain parechovirus, as well as bacteria and parasites. He was untransplanted. A few of these patients have survived viral- initiated on anticoagulation and had complete resolution mediated immune dysregulation early in life and live well of weakness to his baseline. into adulthood. (e natural history of these patients and Subsequently, the patient was referred to our clinic for reasons for their relative longevity are not well understood. reevaluation after 30 years. Immune profiles at this time showed therapeutic IgG troughs and low levels of IgM and In this case report, we present an XLP1 patient who survived into his forties without HSCT and review the literature for IgA. He had normal T cell counts and low B and NK cell counts (Table 1). NK cell cytotoxicity assays revealed normal the natural history of XLP1. spontaneous cytotoxicity but decreased antibody-dependent cytotoxicity (Figure 3). By flow cytometry, we found no SAP 2. Case Presentation + + − + expression in CD3 CD8 T cells and CD3 CD56 NK cells (Figure 4). Full deletion of SH2D1A was revealed by a Our patient was healthy and developed normally until age 6, commercial immunodeficiency panel (https://www.invitae. when he exhibited worsening respiratory symptoms. Lung com/en/physician/tests/08100/). (e patient’s mother was a biopsy revealed mature lymphoplasmacytic infiltrate in the carrier of the same deletion, while his half brother did not alveolar septa consistent with lymphoid interstitial pneu- have the deletion (Figure 5). Unfortunately, our patient’s monia (Figures 1(a) and 1(b)). He received corticosteroids functional status excluded the option of HSCT. and cyclophosphamide for 2 years with significant im- A year after being evaluated at our clinic, our patient provement. At age 12, he developed fever, hep- developed recurrent pulmonary infections followed by atosplenomegaly, lymphadenopathy, and lymphocytosis liver failure and pancytopenia. Bone marrow biopsy was consistent with severe infectious mononucleosis. He had a consistent with classical Hodgkin Lymphoma (Figure 6). protracted hospital course but eventually recovered without He declined chemotherapy and died a few days after developing HLH (Figure 1(c)) and seroconverted to a typical diagnosis. convalescent pattern. Our patient subsequently developed hypogammaglobulinemia and was started on intravenous immunoglobulin (IVIG). 3. Discussion During the same year, his two brothers (7 and 10 years old) developed fevers and respiratory symptoms and were Although the original presentation of our patient and his diagnosed with pulmonary lymphomatoid gran- brothers at our institution 3 decades ago eluded diagnosis, ulomatosis and hypogammaglobinemia. Despite steroid we were able to confirm our patient’s molecular diagnosis of and cyclophosphamide treatment, one brother succumbed XLP1 using flow cytometry and genetic testing. Retro- to HLH in the setting of candidemia, while the other died spectively, our patient displayed most of the classic features of massive gastrointestinal bleeding. (ough XLP1 was of XLP1 in his lifespan including (pulmonary) lympho- considered in the differential diagnosis, it was excluded proliferation, severe EBV infection, dysgammaglobulinemia, due to atypical pulmonary manifestations and lack of EBV and lymphoma. He did not develop HLH at any stage even infections (i.e., negative serologies) in his two brothers when diagnosed with lymphoma at the end of life, and we [11]. suspect that this allowed for his survival into adulthood [11]. After the death of his siblings, at age 13, our patient Although samples of sufficient quality from his sib- experienced recurrent strokes and was found to have lings were not available for genotyping, we can infer necrotizing CNS vasculitis on brain biopsy. He was treated based on their mother’s genetic test that they also had with corticosteroids and interferon-c and recovered with whole sequence deletions of SH2D1A. Given this as- residual left-sided weakness; however, he was lost to fol- sumption, it is noteworthy that the siblings succumbed to low-up. XLP1 during childhood, while their brother survived for In the subsequent years, he retrospectively reported two decades afterwards. (is further supports prior obser- episodes of shingles, one episode of seizure (age 28), vations that XLP1 generally lacks genotype-phenotype transaminitis (age 37), and a deep venous thrombosis (age correlation [10, 12, 13]. However, it is interesting that all 42). He also developed progressive respiratory disease siblings presented with progressive respiratory symptoms (Figure 2(a)) associated with recurrent pneumonia (1-2 due to pulmonary lymphoproliferation that was not as- episodes per year). (is necessitated oxygen therapy and sociated with EBV infection [11]. Our patient had lym- occasional wheelchair dependence for exercise intolerance, phoid interstitial pneumonia (LIP), characterized by thus limiting his quality of life. He continued to receive diffuse lymphocytic infiltration of the alveolar septum monthly IVIG and was started on hydrocortisone for a and pulmonary interstitium. Comparatively, his brothers diagnosis of adrenal insufficiency at age 42. had lymphomatoid granulomatosis (LYG) which in Case Reports in Immunology 3 (a) (b) (c) Figure 1: Histopathology during childhood. (a) Lung biopsy at age 6 revealed mature lymphoplasmacytic infiltrate in the alveolar septa consistent with lymphoid interstitial pneumonia. (b) Lung, higher magnification. (c) Bone marrow biopsy at age 12 with erythroid and eosinophilic hyperplasia and granulocytic hypoplasia; hemophagocytosis was absent. (a) (b) Figure 2: Radiology at age 43. (a) Chest CTscan with diffuse consolidations, bronchiectasis, and cysts. (b) MRI brain showing bilateral areas of acute infarction and left frontal encephalomalacia from prior insult. Table 1: Clinical immunology profile at age 43. Immunoglobulin Levels (Normal range) Immune subsets Total number (103/uL) (Normal range) IgE <2 (≤114 kU/L) Absolute lymphocytes 1330 4500–11000 IgG 1244 (694–1618mg/dL) CD3+T cells 1250 798–2594 IgM 6 (48–271mg/dL) CD19+B cells 40 63–461 IgA <5 (81–463mg/dL) CD3-CD16+CD56+NK cells 39 89–472 (e patient had a therapeutic IgG level but low IgM and IgA levels. Flow cytometry also showed normal T cell counts but low B and NK cell counts. addition included angiitis and focal necrosis [14, 15]. hydrocortisone provided immunomodulatory effects that (ough LIP and LYG are viewed as distinct pathological aided in his surprising recovery. As exemplified by this case, entities, their manifestations in these brothers with the majority of reported CNS vasculitis (8/10) in XLP1 has presumed syngeneic XLP1 beg speculation as to whether no identifiable infectious trigger [20]. (is suggests that CNS these entities exist on a continuum, especially in the setting vasculitis associated with XLP1 has an intrinsic trigger leading to lymphocytic infiltration into cerebral vessels. of primary immunodeficiency. Other rare manifestations of XLP1 include gastritis, skin Our case also represents a rare patient with untrans- lesions, aplastic anemia, and vasculitis [16–19]. Our patient planted XLP1 who lived into mid-adulthood. Literature likely experienced two episodes of CNS vasculitis decades review revealed six additional untransplanted XLP1 patients apart. (e first was biopsy-confirmed during childhood, and who survived into their forties (Table 2) [20–22]. Of the five the second was presumed based on clinical presentation and cases that looked at protein, all had mitigating factors (i.e., imaging at the age of 43 years. After his latest stroke episode, genetic reversion or unstable yet functional protein) that led his neurologic symptoms completely resolved with anti- to residual protein expression. Remarkably, our patient coagulation. We reason that his maintenance IVIG and survived to a similar age without any SAP expression, further 4 Case Reports in Immunology NK spontaneous cytotoxicity 10% cytotoxicity 0 5 10 15 20 25 30 35 40 NK counts (×10 per μL) Patient unstimulated Patient IL-2 stimulated Positive control unstimulated Positive control IL-2 stimulated Patient Control Negative range Normalized Stimulated with Stimulated with Stimulated with results (NKSCC) Unstimulated Unstimulated Unstimulated IL-2 IL-2 IL-2 Calculated NK: target cells ratio for 10% 25 : 1 11 : 1 19 : 1 9 : 1 ≥ 70 : 1 ≥ 20 : 1 cytotoxicity Calculated NK cell 0.040 0.091 0.053 0.111 ≤ 0.011 ≤ 0.05 killing frequency (a) Figure 3: Continued. % spontaneous cytotoxicity Case Reports in Immunology 5 NK antibody-dependent cytotoxicity 5% cytotoxicity 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 NK counts (×10 per μL) Patient unstimulated Patient ritux stimulated Positive control unstimulated Positive control ritux stimulated Normalized Patient Control Negative range results (NKADCC) Stimulated with ritux Stimulated with ritux Stimulated with ritux Calculated NK: target cells ratio for 5% 97 : 1 16 : 1 ≥ 87 : 1 cytotoxicity Calculated NK cell 0.010 0.063 ≤ 0.011 killing frequency (b) Figure 3: NK cell cytotoxicity at age 43. Peripheral blood mononuclear cells (PBMCs) from healthy controls or the patient were used as effector cells and were incubated with target cells. (a) Target cells were the K562 monocytic cell line lacking MHC class I. Spontaneous cytotoxicity against these target cells was measured following a 4-hour stimulation±IL-2. In the absence of IL-2, to lyse 10% of target cells, the patient sample required 25 NK cells per one target cell (25:1, NK: target cell ratio). Comparatively, the control required 19 NK cells per one target cell (19:1). In the presence of IL-2, the patient sample required 11 NK cells per one target cell (11:1) and the control required 9 NK cells per one target cell (9:1). (b) Target cells were human lymphoblast-like Raji B cells that express MHC class I CD19 and CD20. Antibody-dependent NK cell cytotoxicity against these target cells was measured following a 4-hour stimulation±rituximab. No cyto- toxicity was observed in the absence of rituximab. In the presence of rituximab, to lyse 5% of target cells, the patient sample required 97 NK cells per one target cell (97:1), whereas the control required 16 NK cells per one target cell (16:1). (is test was performed in a CLIA- certified laboratory. % spontaneous cytotoxicity 6 Case Reports in Immunology Healthy control Patient 219 292 Isotype Isotype Anti-SAP Anti-SAP control control + + CD3 CD8 T cells 1 2 3 1 2 3 10 10 10 10 10 10 Anti-SAP Anti-SAP 31 19 Isotype Anti-SAP Isotype Anti-SAP control control – + CD3 CD56 NK cells 1 2 3 1 2 3 10 10 10 10 10 10 Anti-SAP Anti-SAP + + Figure 4: Flow cytometry at age 43. Isotype staining is shaded in gray. SAP staining is shown in color: red in CD3 CD8 Tcells and blue in − + CD3 CD56 NK cells. A healthy control is shown for reference. (is figure is representative of repeated tests on two separate instances as performed in a CLIA-certified laboratory. ⊖ SH2D1A ⊕ SH2D1A mutation mutation 6 y 8 y 44 y ⊖ SH2D1A ⊕ SH2D1A ? ? mutation mutation Figure 5: Family history with SH2D1A genotype. A full deletion of SH2D1A was detected using a commercial immunodeficiency panel (https://www.invitae.com/en/physician/tests/08100/) in the patient and his mother, while his half brother did not have the deletion. (e arrow demarcates the case report patient. emphasizing the lack of genotype-phenotype correlation. Even with modern medical advances, XLP1 mortality Instead, the shared predictor of relative longevity for these and morbidity remain high as seen in our patient. Despite XLP1 patients is that they never developed HLH. (e one surviving life-threatening childhood manifestations and patient in this group who did develop HLH at age 49 then being maintained on lifelong IVIG therapy, he suffered from succumbed to it [22]. Otherwise, the mean age of survival for neurologic deficits and progressive lung disease and even- untransplanted XLP1 patients is 7.5 years with 81.3% tually died of lymphoma. Similarly, recent published cases of mortality from HLH [10]. XLP1 patients either do not survive initial childhood Count Count Count Count Case Reports in Immunology 7 H&E CD15 CD30 PAX5 MUM1 CD20 Figure 6: Bone marrow biopsy at age 43. (ere are large atypical cells on H&E, with a typical staining pattern for classical Hodgkin lymphoma. (e neoplastic cells were positive for CD15, CD30, PAX5, and MUM1, while CD20 was negative. Table 2: Published reports of XLP1 cases with relative longevity (age >40 years). Age at Age at SH2D1A SAP clinical death or Status at Clinical manifestations SAP Genetic IVIG mutation mutation Reference onset report publication (age in years) expression reversion (gene) (protein) (years) (years) Premature Clinical EBV (18) Blackburn 49 51 Deceased − c.35G>T p.Ser12Ile degradation Unknown CNS vasculitis (49) et al. [20] but functional Premature Diffuse large B-cell Blackburn 59 65 Deceased − c.35G>T p.Ser12Ile degradation Unknown lymphoma (64) et al. [20] but functional Cerebral B-cell lymphoma (41) Hervier 41 44 Alive + c.462C>T p.Arg55X Not done Unknown Hypogammaglobulinemia et al. [21] (43) Clinical EBV (17) Palendira 17 45 Alive Hypogammaglobulinemia + c.259T>C p.Phe87Ser Deficient Yes et al. [22] (26) B-cell lymphoma (10) Clinical EBV (19) Hypogammaglobulinemia Palendira 10 49 Deceased (19) − c.161A>G p.Tyr54Cys Deficient Yes et al. [22] Meningitis (19) Lymphoproliferation (40) HLH (49) Clinical EBV (20) Palendira 20 52 Alive Hypogammaglobulinemia + c.259T>C p.Phe87Ser Deficient Yes et al. [22] (21) Lymphoid interstitial pneumonia (6) Clinical EBV (12) No 6 44 Deceased Hypogammaglobulinemia + Deletion No protein No (is study expression (12) CNS vasculitis (13, 43) Hodgkin lymphoma (44) ∗ # (e two cases from Blackburn et al. [20] were brothers. Genetic reversion is defined as a secondary mutation that counteracts the effects of the primary mutation, thereby reversing the phenotype back to wild type. 8 Case Reports in Immunology [8] D. Purtilo, J. S. Yang, C. Cassel et al., “X-linked recessive manifestations of XLP1 or succumb to complications in progressive combined variable immunodeficiency (duncan’s mid-adulthood [10, 12, 18, 20–27]. (is remains an im- disease),” ,e Lancet, vol. 305, no. 7913, pp. 935–941, 1975. portant point to emphasize during shared decision making [9] L. L. Williams, M. K. Brenner, R. A. Krance et al., “Correction with newly diagnosed patients with XLP1 who are eligible of Duncan’s syndrome by allogeneic bone marrow trans- for HSCT. plantation,” ,e Lancet, vol. 342, no. 8871, pp. 587–588, Sep. Data Availability [10] C. Booth, K. C. Gilmour, P. Veys et al., “X-linked lympho- proliferative disease due to SAP/SH2D1A deficiency: A All immunology assay data are available upon request. multicenter study on the manifestations, management and outcome of the disease,” Blood, vol.117, no.1, pp. 53–62, 2011. Conflicts of Interest [11] B. B. Rogers, I. Browning, H. Rosenblatt et al., “A familial lymphoproliferative disorder presenting with primary pul- (e authors declare that they have no conflicts of interest. monary manifestations,” American Review of Respiratory Disease, vol. 145, no. 1, pp. 203–208, 1992. [12] Z. Nademi, N. Radwan, K. Rao, K. Gilmour, A. Worth, and Authors’ Contributions C. Booth, “Different phenotypic presentations of X-linked Tiphanie P. Vogel and Joud Hajjar contributed equally as lymphoproliferative disease in siblings with identical muta- tions,” Journal of Clinical Immunology, vol. 39, no. 5, senior authors to this manuscript. pp. 523–526, 2019. [13] H. Kanegane, X. Yang, M. Zhao et al., “Clinical features and Acknowledgments outcome of X-linked lymphoproliferative syndrome type 1 (SAP deficiency) in Japan identified by the combination of (e authors respectfully acknowledge participation of the flow cytometric assay and genetic analysis,” Pediatric Allergy patient and his family members in the development of this and Immunology, vol. 23, no. 5, pp. 488–493, 2012. case report. (e authors also acknowledge the support of the [14] T. E. King, “Pulmonary lymphomatoid granulomatosis,” Ad- Pediatrician-Scientist Program at the Baylor College of vances in Anatomic Pathology, 1999, https://www.uptodate. Medicine. (e authors also acknowledge the editorial com/contents/pulmonary-lymphomatoid-granulomatosis. contribution of Dr. Susan Marriott and BioScience Writers. [15] L. R. Young, “Lymphocytic interstitial pneumonia in chil- (e work and writing for this case report were performed as dren,” 2020, https://www.uptodate.com/contents/lymphocytic- part of the employment of the authors by Texas Children’s interstitial-pneumonia-in-children?search�xlp1&topicRef� Hospital and Baylor College of Medicine. Genetic testing for 4361&source�see_link#H3. this patient was generously funded by the Jeffrey Modell [16] H. Kanegane, Y. Ito, K. Ohshima et al., “X-linked lympho- proliferative syndrome presenting with systemic lymphocytic Foundation through Texas Children’s Hospital. vasculitis,” American Journal of Hematology, vol. 78, no. 2, pp. 130–133, 2005. References [17] A.-L. Rougemont, J.-C. Fournet, S. R. Martin et al., “Chronic active gastritis in X-linked lymphoproliferative disease,” ,e [1] D. T. 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The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor

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Copyright © 2020 Yike Jiang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2020/8841571
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Abstract

Hindawi Case Reports in Immunology Volume 2020, Article ID 8841571, 9 pages https://doi.org/10.1155/2020/8841571 Case Report The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor 1 2 3 1 4 Yike Jiang , Mihail Firan, Sarada L. Nandiwada, Anaid Reyes, Rebecca A. Marsh, 1 3 Tiphanie P. Vogel, and Joud Hajjar Texas Children’s Hospital and Baylor College of Medicine, Department of Pediatrics, Section of Rheumatology, Houston, TX, USA Texas Children’s Hospital and Baylor College of Medicine, Department of Pathology and Immunology, Houston, TX, USA Texas Children’s Hospital and Baylor College of Medicine, Department of Pediatrics, Section of Immunology, Allergy and Retrovirology, Houston, TX, USA Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Department of Pediatrics, Section of Bone Marrow Transplantation and Immune Deficiency, Cincinnati, OH, USA Correspondence should be addressed to Joud Hajjar; joud.hajjar@bcm.edu Received 27 June 2020; Revised 31 July 2020; Accepted 12 August 2020; Published 27 August 2020 Academic Editor: Claudio Pignata Copyright © 2020 Yike Jiang et al. (is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency characterized by EBV-triggered immune dysregulation, lymphoproliferation, dysgammaglobulinemia, and lymphoma. Early childhood mortality from overwhelming inflammation is expected in most patients. (e only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCTon an asymptomatic patient remains debatable. (is uncertainty arises because the natural history of XLP1 patients without transplantation is not clear. In this case report, we present the natural history of XLP1 in a 43-year-old male patient who did not receive HSCT. We also review the literature on untransplanted XLP1 patients who lived into mid-adulthood. Despite surviving childhood presentations that are typically fatal, we found that these rare patients remain susceptible to manifestations of XLP1 decades later. phosphorylation of the SLAM receptor and recruitment of 1. Introduction downstream signaling molecules, triggering immune cell X-linked lymphoproliferative disease (XLP1) is a primary activation. When SAP is absent in XLP1, these tyrosines on immunodeficiency characterized by severe immune dysre- SLAM bind to strong inhibitory molecules that abrogate gulation triggered by viral infection (commonly EBV), downstream signaling and activation [3]. (e molecular hypogammaglobulinemia, and lymphoma. (is disease is imbalance in SAP deficiency impairs T and NK cell rare with an estimated incidence of 1–3 in 1 ×10 males [1], a function and abolishes NKTdevelopment. Mechanistically, likely underestimate due to the significant risk of early diminished T cell help in germinal centers, compromised childhood death. immunosurveillance, reduced cytotoxicity, and impaired XLP1 is caused by a deficiency in signaling lymphocyte T cell apoptosis leads to dysgammaglobulinemia, lym- activation molecule- (SLAM-) associated protein (SAP). phomas, fulminant infectious mononucleosis, and hemo- SLAM family members are signaling receptors broadly phagocytic lymphohistiocytosis (HLH)—the classic expressed on hematopoietic cells. SAP binds to the in- features of XLP1 [3]. tracellular domain of SLAM proteins, serving as a mo- Diagnosis of XLP1 relies on genetic testing for mutations lecular switch that toggles between cellular activation and in SH2D1A, but rapid immunologic testing is often critical at inhibition [2]. Normally, SAP promotes tyrosine the time of presentation. (is includes the absence of SAP 2 Case Reports in Immunology At age 43, he developed sudden vision change, protein expression by flow cytometry, reduced ex vivo NK cell killing, and the absence of NKT cells [4–7]. headache, right-sided weakness, and seizure. MRI of the brain revealed bilateral areas of acute infarction Since the disease’s discovery in 1975 [8], the only cu- rative therapy for XLP1 is hematopoietic stem cell transplant (Figure 2(b)).Additional evaluation failed to identify a (HSCT). First successfully performed for XLP1 in 1993 [9], primary thrombus. Infectious evaluation was negative for HSCT has since significantly improved overall survival [10]. acute infections such as EBV, VZV, CMV, HHV6, and However, there are rare XLP1 patients who remain parechovirus, as well as bacteria and parasites. He was untransplanted. A few of these patients have survived viral- initiated on anticoagulation and had complete resolution mediated immune dysregulation early in life and live well of weakness to his baseline. into adulthood. (e natural history of these patients and Subsequently, the patient was referred to our clinic for reasons for their relative longevity are not well understood. reevaluation after 30 years. Immune profiles at this time showed therapeutic IgG troughs and low levels of IgM and In this case report, we present an XLP1 patient who survived into his forties without HSCT and review the literature for IgA. He had normal T cell counts and low B and NK cell counts (Table 1). NK cell cytotoxicity assays revealed normal the natural history of XLP1. spontaneous cytotoxicity but decreased antibody-dependent cytotoxicity (Figure 3). By flow cytometry, we found no SAP 2. Case Presentation + + − + expression in CD3 CD8 T cells and CD3 CD56 NK cells (Figure 4). Full deletion of SH2D1A was revealed by a Our patient was healthy and developed normally until age 6, commercial immunodeficiency panel (https://www.invitae. when he exhibited worsening respiratory symptoms. Lung com/en/physician/tests/08100/). (e patient’s mother was a biopsy revealed mature lymphoplasmacytic infiltrate in the carrier of the same deletion, while his half brother did not alveolar septa consistent with lymphoid interstitial pneu- have the deletion (Figure 5). Unfortunately, our patient’s monia (Figures 1(a) and 1(b)). He received corticosteroids functional status excluded the option of HSCT. and cyclophosphamide for 2 years with significant im- A year after being evaluated at our clinic, our patient provement. At age 12, he developed fever, hep- developed recurrent pulmonary infections followed by atosplenomegaly, lymphadenopathy, and lymphocytosis liver failure and pancytopenia. Bone marrow biopsy was consistent with severe infectious mononucleosis. He had a consistent with classical Hodgkin Lymphoma (Figure 6). protracted hospital course but eventually recovered without He declined chemotherapy and died a few days after developing HLH (Figure 1(c)) and seroconverted to a typical diagnosis. convalescent pattern. Our patient subsequently developed hypogammaglobulinemia and was started on intravenous immunoglobulin (IVIG). 3. Discussion During the same year, his two brothers (7 and 10 years old) developed fevers and respiratory symptoms and were Although the original presentation of our patient and his diagnosed with pulmonary lymphomatoid gran- brothers at our institution 3 decades ago eluded diagnosis, ulomatosis and hypogammaglobinemia. Despite steroid we were able to confirm our patient’s molecular diagnosis of and cyclophosphamide treatment, one brother succumbed XLP1 using flow cytometry and genetic testing. Retro- to HLH in the setting of candidemia, while the other died spectively, our patient displayed most of the classic features of massive gastrointestinal bleeding. (ough XLP1 was of XLP1 in his lifespan including (pulmonary) lympho- considered in the differential diagnosis, it was excluded proliferation, severe EBV infection, dysgammaglobulinemia, due to atypical pulmonary manifestations and lack of EBV and lymphoma. He did not develop HLH at any stage even infections (i.e., negative serologies) in his two brothers when diagnosed with lymphoma at the end of life, and we [11]. suspect that this allowed for his survival into adulthood [11]. After the death of his siblings, at age 13, our patient Although samples of sufficient quality from his sib- experienced recurrent strokes and was found to have lings were not available for genotyping, we can infer necrotizing CNS vasculitis on brain biopsy. He was treated based on their mother’s genetic test that they also had with corticosteroids and interferon-c and recovered with whole sequence deletions of SH2D1A. Given this as- residual left-sided weakness; however, he was lost to fol- sumption, it is noteworthy that the siblings succumbed to low-up. XLP1 during childhood, while their brother survived for In the subsequent years, he retrospectively reported two decades afterwards. (is further supports prior obser- episodes of shingles, one episode of seizure (age 28), vations that XLP1 generally lacks genotype-phenotype transaminitis (age 37), and a deep venous thrombosis (age correlation [10, 12, 13]. However, it is interesting that all 42). He also developed progressive respiratory disease siblings presented with progressive respiratory symptoms (Figure 2(a)) associated with recurrent pneumonia (1-2 due to pulmonary lymphoproliferation that was not as- episodes per year). (is necessitated oxygen therapy and sociated with EBV infection [11]. Our patient had lym- occasional wheelchair dependence for exercise intolerance, phoid interstitial pneumonia (LIP), characterized by thus limiting his quality of life. He continued to receive diffuse lymphocytic infiltration of the alveolar septum monthly IVIG and was started on hydrocortisone for a and pulmonary interstitium. Comparatively, his brothers diagnosis of adrenal insufficiency at age 42. had lymphomatoid granulomatosis (LYG) which in Case Reports in Immunology 3 (a) (b) (c) Figure 1: Histopathology during childhood. (a) Lung biopsy at age 6 revealed mature lymphoplasmacytic infiltrate in the alveolar septa consistent with lymphoid interstitial pneumonia. (b) Lung, higher magnification. (c) Bone marrow biopsy at age 12 with erythroid and eosinophilic hyperplasia and granulocytic hypoplasia; hemophagocytosis was absent. (a) (b) Figure 2: Radiology at age 43. (a) Chest CTscan with diffuse consolidations, bronchiectasis, and cysts. (b) MRI brain showing bilateral areas of acute infarction and left frontal encephalomalacia from prior insult. Table 1: Clinical immunology profile at age 43. Immunoglobulin Levels (Normal range) Immune subsets Total number (103/uL) (Normal range) IgE <2 (≤114 kU/L) Absolute lymphocytes 1330 4500–11000 IgG 1244 (694–1618mg/dL) CD3+T cells 1250 798–2594 IgM 6 (48–271mg/dL) CD19+B cells 40 63–461 IgA <5 (81–463mg/dL) CD3-CD16+CD56+NK cells 39 89–472 (e patient had a therapeutic IgG level but low IgM and IgA levels. Flow cytometry also showed normal T cell counts but low B and NK cell counts. addition included angiitis and focal necrosis [14, 15]. hydrocortisone provided immunomodulatory effects that (ough LIP and LYG are viewed as distinct pathological aided in his surprising recovery. As exemplified by this case, entities, their manifestations in these brothers with the majority of reported CNS vasculitis (8/10) in XLP1 has presumed syngeneic XLP1 beg speculation as to whether no identifiable infectious trigger [20]. (is suggests that CNS these entities exist on a continuum, especially in the setting vasculitis associated with XLP1 has an intrinsic trigger leading to lymphocytic infiltration into cerebral vessels. of primary immunodeficiency. Other rare manifestations of XLP1 include gastritis, skin Our case also represents a rare patient with untrans- lesions, aplastic anemia, and vasculitis [16–19]. Our patient planted XLP1 who lived into mid-adulthood. Literature likely experienced two episodes of CNS vasculitis decades review revealed six additional untransplanted XLP1 patients apart. (e first was biopsy-confirmed during childhood, and who survived into their forties (Table 2) [20–22]. Of the five the second was presumed based on clinical presentation and cases that looked at protein, all had mitigating factors (i.e., imaging at the age of 43 years. After his latest stroke episode, genetic reversion or unstable yet functional protein) that led his neurologic symptoms completely resolved with anti- to residual protein expression. Remarkably, our patient coagulation. We reason that his maintenance IVIG and survived to a similar age without any SAP expression, further 4 Case Reports in Immunology NK spontaneous cytotoxicity 10% cytotoxicity 0 5 10 15 20 25 30 35 40 NK counts (×10 per μL) Patient unstimulated Patient IL-2 stimulated Positive control unstimulated Positive control IL-2 stimulated Patient Control Negative range Normalized Stimulated with Stimulated with Stimulated with results (NKSCC) Unstimulated Unstimulated Unstimulated IL-2 IL-2 IL-2 Calculated NK: target cells ratio for 10% 25 : 1 11 : 1 19 : 1 9 : 1 ≥ 70 : 1 ≥ 20 : 1 cytotoxicity Calculated NK cell 0.040 0.091 0.053 0.111 ≤ 0.011 ≤ 0.05 killing frequency (a) Figure 3: Continued. % spontaneous cytotoxicity Case Reports in Immunology 5 NK antibody-dependent cytotoxicity 5% cytotoxicity 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 NK counts (×10 per μL) Patient unstimulated Patient ritux stimulated Positive control unstimulated Positive control ritux stimulated Normalized Patient Control Negative range results (NKADCC) Stimulated with ritux Stimulated with ritux Stimulated with ritux Calculated NK: target cells ratio for 5% 97 : 1 16 : 1 ≥ 87 : 1 cytotoxicity Calculated NK cell 0.010 0.063 ≤ 0.011 killing frequency (b) Figure 3: NK cell cytotoxicity at age 43. Peripheral blood mononuclear cells (PBMCs) from healthy controls or the patient were used as effector cells and were incubated with target cells. (a) Target cells were the K562 monocytic cell line lacking MHC class I. Spontaneous cytotoxicity against these target cells was measured following a 4-hour stimulation±IL-2. In the absence of IL-2, to lyse 10% of target cells, the patient sample required 25 NK cells per one target cell (25:1, NK: target cell ratio). Comparatively, the control required 19 NK cells per one target cell (19:1). In the presence of IL-2, the patient sample required 11 NK cells per one target cell (11:1) and the control required 9 NK cells per one target cell (9:1). (b) Target cells were human lymphoblast-like Raji B cells that express MHC class I CD19 and CD20. Antibody-dependent NK cell cytotoxicity against these target cells was measured following a 4-hour stimulation±rituximab. No cyto- toxicity was observed in the absence of rituximab. In the presence of rituximab, to lyse 5% of target cells, the patient sample required 97 NK cells per one target cell (97:1), whereas the control required 16 NK cells per one target cell (16:1). (is test was performed in a CLIA- certified laboratory. % spontaneous cytotoxicity 6 Case Reports in Immunology Healthy control Patient 219 292 Isotype Isotype Anti-SAP Anti-SAP control control + + CD3 CD8 T cells 1 2 3 1 2 3 10 10 10 10 10 10 Anti-SAP Anti-SAP 31 19 Isotype Anti-SAP Isotype Anti-SAP control control – + CD3 CD56 NK cells 1 2 3 1 2 3 10 10 10 10 10 10 Anti-SAP Anti-SAP + + Figure 4: Flow cytometry at age 43. Isotype staining is shaded in gray. SAP staining is shown in color: red in CD3 CD8 Tcells and blue in − + CD3 CD56 NK cells. A healthy control is shown for reference. (is figure is representative of repeated tests on two separate instances as performed in a CLIA-certified laboratory. ⊖ SH2D1A ⊕ SH2D1A mutation mutation 6 y 8 y 44 y ⊖ SH2D1A ⊕ SH2D1A ? ? mutation mutation Figure 5: Family history with SH2D1A genotype. A full deletion of SH2D1A was detected using a commercial immunodeficiency panel (https://www.invitae.com/en/physician/tests/08100/) in the patient and his mother, while his half brother did not have the deletion. (e arrow demarcates the case report patient. emphasizing the lack of genotype-phenotype correlation. Even with modern medical advances, XLP1 mortality Instead, the shared predictor of relative longevity for these and morbidity remain high as seen in our patient. Despite XLP1 patients is that they never developed HLH. (e one surviving life-threatening childhood manifestations and patient in this group who did develop HLH at age 49 then being maintained on lifelong IVIG therapy, he suffered from succumbed to it [22]. Otherwise, the mean age of survival for neurologic deficits and progressive lung disease and even- untransplanted XLP1 patients is 7.5 years with 81.3% tually died of lymphoma. Similarly, recent published cases of mortality from HLH [10]. XLP1 patients either do not survive initial childhood Count Count Count Count Case Reports in Immunology 7 H&E CD15 CD30 PAX5 MUM1 CD20 Figure 6: Bone marrow biopsy at age 43. (ere are large atypical cells on H&E, with a typical staining pattern for classical Hodgkin lymphoma. (e neoplastic cells were positive for CD15, CD30, PAX5, and MUM1, while CD20 was negative. Table 2: Published reports of XLP1 cases with relative longevity (age >40 years). Age at Age at SH2D1A SAP clinical death or Status at Clinical manifestations SAP Genetic IVIG mutation mutation Reference onset report publication (age in years) expression reversion (gene) (protein) (years) (years) Premature Clinical EBV (18) Blackburn 49 51 Deceased − c.35G>T p.Ser12Ile degradation Unknown CNS vasculitis (49) et al. [20] but functional Premature Diffuse large B-cell Blackburn 59 65 Deceased − c.35G>T p.Ser12Ile degradation Unknown lymphoma (64) et al. [20] but functional Cerebral B-cell lymphoma (41) Hervier 41 44 Alive + c.462C>T p.Arg55X Not done Unknown Hypogammaglobulinemia et al. [21] (43) Clinical EBV (17) Palendira 17 45 Alive Hypogammaglobulinemia + c.259T>C p.Phe87Ser Deficient Yes et al. [22] (26) B-cell lymphoma (10) Clinical EBV (19) Hypogammaglobulinemia Palendira 10 49 Deceased (19) − c.161A>G p.Tyr54Cys Deficient Yes et al. [22] Meningitis (19) Lymphoproliferation (40) HLH (49) Clinical EBV (20) Palendira 20 52 Alive Hypogammaglobulinemia + c.259T>C p.Phe87Ser Deficient Yes et al. [22] (21) Lymphoid interstitial pneumonia (6) Clinical EBV (12) No 6 44 Deceased Hypogammaglobulinemia + Deletion No protein No (is study expression (12) CNS vasculitis (13, 43) Hodgkin lymphoma (44) ∗ # (e two cases from Blackburn et al. [20] were brothers. Genetic reversion is defined as a secondary mutation that counteracts the effects of the primary mutation, thereby reversing the phenotype back to wild type. 8 Case Reports in Immunology [8] D. Purtilo, J. S. Yang, C. Cassel et al., “X-linked recessive manifestations of XLP1 or succumb to complications in progressive combined variable immunodeficiency (duncan’s mid-adulthood [10, 12, 18, 20–27]. (is remains an im- disease),” ,e Lancet, vol. 305, no. 7913, pp. 935–941, 1975. portant point to emphasize during shared decision making [9] L. L. Williams, M. K. Brenner, R. A. 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