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

Authors: Yike Jiang; Mihail Firan; Sarada L. Nandiwada; Anaid Reyes; Rebecca A. Marsh; Tiphanie P. Vogel; Joud Hajjar
Journal: Case Reports in Immunology
 (2020)

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## Abstract

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. The only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCT on an asymptomatic patient remains debatable. This 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.


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## Body

## 1. Introduction

X-linked lymphoproliferative disease (XLP1) is a primary immunodeficiency characterized by severe immune dysregulation triggered by viral infection (commonly EBV), hypogammaglobulinemia, and lymphoma. This disease is rare with an estimated incidence of 1–3 in 1 × 106 males [1], a likely underestimate due to the significant risk of early childhood death.XLP1 is caused by a deficiency in signaling lymphocyte activation molecule- (SLAM-) associated protein (SAP). SLAM family members are signaling receptors broadly expressed on hematopoietic cells. SAP binds to the intracellular domain of SLAM proteins, serving as a molecular switch that toggles between cellular activation and inhibition [2]. Normally, SAP promotes tyrosine phosphorylation of the SLAM receptor and recruitment of downstream signaling molecules, triggering immune cell activation. When SAP is absent in XLP1, these tyrosines on SLAM bind to strong inhibitory molecules that abrogate downstream signaling and activation [3]. The molecular imbalance in SAP deficiency impairs T and NK cell function and abolishes NKT development. Mechanistically, diminished T cell help in germinal centers, compromised immunosurveillance, reduced cytotoxicity, and impaired T cell apoptosis leads to dysgammaglobulinemia, lymphomas, fulminant infectious mononucleosis, and hemophagocytic lymphohistiocytosis (HLH)—the classic features of XLP1 [3].Diagnosis of XLP1 relies on genetic testing for mutations inSH2D1A, but rapid immunologic testing is often critical at the time of presentation. This includes the absence of SAP protein expression by flow cytometry, reduced ex vivo NK cell killing, and the absence of NKT cells [4–7].Since the disease’s discovery in 1975 [8], the only curative therapy for XLP1 is hematopoietic stem cell transplant (HSCT). First successfully performed for XLP1 in 1993 [9], HSCT has since significantly improved overall survival [10]. However, there are rare XLP1 patients who remain untransplanted. A few of these patients have survived viral-mediated immune dysregulation early in life and live well into adulthood. The natural history of these patients and reasons for their relative longevity are not well understood. In this case report, we present an XLP1 patient who survived into his forties without HSCT and review the literature for the natural history of XLP1.


## 2. Case Presentation

Our patient was healthy and developed normally until age 6, when he exhibited worsening respiratory symptoms. Lung biopsy revealed mature lymphoplasmacytic infiltrate in the alveolar septa consistent with lymphoid interstitial pneumonia (Figures1(a) and 1(b)). He received corticosteroids and cyclophosphamide for 2 years with significant improvement. At age 12, he developed fever, hepatosplenomegaly, lymphadenopathy, and lymphocytosis consistent with severe infectious mononucleosis. He had a protracted hospital course but eventually recovered without developing HLH (Figure 1(c)) and seroconverted to a typical convalescent pattern. Our patient subsequently developed hypogammaglobulinemia and was started on intravenous immunoglobulin (IVIG).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)(c)During the same year, his two brothers (7 and 10 years old) developed fevers and respiratory symptoms and were diagnosed with pulmonary lymphomatoid granulomatosis and hypogammaglobinemia. Despite steroid and cyclophosphamide treatment, one brother succumbed to HLH in the setting of candidemia, while the other died of massive gastrointestinal bleeding. Though XLP1 was considered in the differential diagnosis, it was excluded due to atypical pulmonary manifestations and lack of EBV infections (i.e., negative serologies) in his two brothers [11].After the death of his siblings, at age 13, our patient experienced recurrent strokes and was found to have necrotizing CNS vasculitis on brain biopsy. He was treated with corticosteroids and interferon-γ and recovered with residual left-sided weakness; however, he was lost to follow-up.In the subsequent years, he retrospectively reported two episodes of shingles, one episode of seizure (age 28), transaminitis (age 37), and a deep venous thrombosis (age 42). He also developed progressive respiratory disease (Figure2(a)) associated with recurrent pneumonia (1-2 episodes per year). This necessitated oxygen therapy and occasional wheelchair dependence for exercise intolerance, thus limiting his quality of life. He continued to receive monthly IVIG and was started on hydrocortisone for a diagnosis of adrenal insufficiency at age 42.Figure 2
Radiology at age 43. (a) Chest CT scan with diffuse consolidations, bronchiectasis, and cysts. (b) MRI brain showing bilateral areas of acute infarction and left frontal encephalomalacia from prior insult.
(a)(b)At age 43, he developed sudden vision change, headache, right-sided weakness, and seizure. MRI of the brain revealed bilateral areas of acute infarction (Figure2(b)).Additional evaluation failed to identify a primary thrombus. Infectious evaluation was negative for acute infections such as EBV, VZV, CMV, HHV6, and parechovirus, as well as bacteria and parasites. He was initiated on anticoagulation and had complete resolution of weakness to his baseline.Subsequently, the patient was referred to our clinic for reevaluation after 30 years. Immune profiles at this time showed therapeutic IgG troughs and low levels of IgM and IgA. He had normal T cell counts and low B and NK cell counts (Table1). NK cell cytotoxicity assays revealed normal spontaneous cytotoxicity but decreased antibody-dependent cytotoxicity (Figure 3). By flow cytometry, we found no SAP expression in CD3+CD8+ T cells and CD3−CD56+ NK cells (Figure 4). Full deletion of SH2D1A was revealed by a commercial immunodeficiency panel (https://www.invitae.com/en/physician/tests/08100/). The patient’s mother was a carrier of the same deletion, while his half brother did not have the deletion (Figure 5). Unfortunately, our patient’s functional status excluded the option of HSCT.Table 1
Clinical immunology profile at age 43.
ImmunoglobulinLevels(Normal range)Immune subsetsTotal number (103/uL)(Normal range)IgE<2(≤114 kU/L)Absolute lymphocytes13304500–11000IgG1244(694–1618 mg/dL)CD3 + T cells1250798–2594IgM6(48–271 mg/dL)CD19+ B cells4063–461IgA<5(81–463 mg/dL)CD3-CD16+ CD56+ NK cells3989–472The 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.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 cytotoxicity 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). This test was performed in a CLIA-certified laboratory.
(a)(b)Figure 4
Flow cytometry at age 43. Isotype staining is shaded in gray. SAP staining is shown in color: red in CD3+CD8+ T cells and blue in CD3−CD56+ NK cells. A healthy control is shown for reference. This figure is representative of repeated tests on two separate instances as performed in a CLIA-certified laboratory.Figure 5
Family history withSH2D1A 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. The arrow demarcates the case report patient.A year after being evaluated at our clinic, our patient developed recurrent pulmonary infections followed by liver failure and pancytopenia. Bone marrow biopsy was consistent with classical Hodgkin Lymphoma (Figure6). He declined chemotherapy and died a few days after diagnosis.Figure 6
Bone marrow biopsy at age 43. There are large atypical cells on H&E, with a typical staining pattern for classical Hodgkin lymphoma. The neoplastic cells were positive for CD15, CD30, PAX5, and MUM1, while CD20 was negative.


## 3. Discussion

Although the original presentation of our patient and his brothers at our institution 3 decades ago eluded diagnosis, we were able to confirm our patient’s molecular diagnosis of XLP1 using flow cytometry and genetic testing. Retrospectively, our patient displayed most of the classic features of XLP1 in his lifespan including (pulmonary) lymphoproliferation, severe EBV infection, dysgammaglobulinemia, and lymphoma. He did not develop HLH at any stage even when diagnosed with lymphoma at the end of life, and we suspect that this allowed for his survival into adulthood [11].Although samples of sufficient quality from his siblings were not available for genotyping, we can infer based on their mother’s genetic test that they also had whole sequence deletions ofSH2D1A. Given this assumption, it is noteworthy that the siblings succumbed to XLP1 during childhood, while their brother survived for decades afterwards. This further supports prior observations that XLP1 generally lacks genotype-phenotype correlation [10, 12, 13]. However, it is interesting that all siblings presented with progressive respiratory symptoms due to pulmonary lymphoproliferation that was not associated with EBV infection [11]. Our patient had lymphoid interstitial pneumonia (LIP), characterized by diffuse lymphocytic infiltration of the alveolar septum and pulmonary interstitium. Comparatively, his brothers had lymphomatoid granulomatosis (LYG) which in addition included angiitis and focal necrosis [14, 15]. Though LIP and LYG are viewed as distinct pathological entities, their manifestations in these brothers with presumed syngeneic XLP1 beg speculation as to whether these entities exist on a continuum, especially in the setting of primary immunodeficiency.Other rare manifestations of XLP1 include gastritis, skin lesions, aplastic anemia, and vasculitis [16–19]. Our patient likely experienced two episodes of CNS vasculitis decades apart. The first was biopsy-confirmed during childhood, and the second was presumed based on clinical presentation and imaging at the age of 43 years. After his latest stroke episode, his neurologic symptoms completely resolved with anticoagulation. We reason that his maintenance IVIG and hydrocortisone provided immunomodulatory effects that aided in his surprising recovery. As exemplified by this case, the majority of reported CNS vasculitis (8/10) in XLP1 has no identifiable infectious trigger [20]. This suggests that CNS vasculitis associated with XLP1 has an intrinsic trigger leading to lymphocytic infiltration into cerebral vessels.Our case also represents a rare patient with untransplanted XLP1 who lived into mid-adulthood. Literature review revealed six additional untransplanted XLP1 patients who survived into their forties (Table2) [20–22]. Of the five cases that looked at protein, all had mitigating factors (i.e., genetic reversion or unstable yet functional protein) that led to residual protein expression. Remarkably, our patient survived to a similar age without any SAP expression, further emphasizing the lack of genotype-phenotype correlation. Instead, the shared predictor of relative longevity for these XLP1 patients is that they never developed HLH. The one patient in this group who did develop HLH at age 49 then succumbed to it [22]. Otherwise, the mean age of survival for untransplanted XLP1 patients is 7.5 years with 81.3% mortality from HLH [10].Table 2
Published reports of XLP1 cases with relative longevity (age >40 years).
Age at clinical onset (years)Age at death or report (years)Status at publicationClinical manifestations (age in years)IVIGSH2D1A mutation (gene)SAP mutation (protein)SAP expressionGenetic reversion#Reference49∗51DeceasedClinical EBV (18)CNS vasculitis (49)−c.35 G > Tp.Ser12IlePremature degradation but functionalUnknownBlackburn et al. [20]59∗65DeceasedDiffuse large B-cell lymphoma (64)−c.35 G > Tp.Ser12IlePremature degradation but functionalUnknownBlackburn et al. [20]4144AliveCerebral B-cell lymphoma (41)Hypogammaglobulinemia (43)+c.462 C > Tp.Arg55XNot doneUnknownHervier et al. [21]1745AliveClinical EBV (17)Hypogammaglobulinemia (26)+c.259 T > Cp.Phe87SerDeficientYesPalendira et al. [22]1049DeceasedB-cell lymphoma (10)Clinical EBV (19)Hypogammaglobulinemia (19)Meningitis (19)Lymphoproliferation (40)HLH (49)−c.161 A > Gp.Tyr54CysDeficientYesPalendira et al. [22]2052AliveClinical EBV (20)Hypogammaglobulinemia (21)+c.259 T > Cp.Phe87SerDeficientYesPalendira et al. [22]644DeceasedLymphoid interstitial pneumonia (6)Clinical EBV (12)Hypogammaglobulinemia (12)CNS vasculitis (13, 43)Hodgkin lymphoma (44)+DeletionNo proteinNo expressionNoThis study∗The 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.Even with modern medical advances, XLP1 mortality and morbidity remain high as seen in our patient. Despite surviving life-threatening childhood manifestations and being maintained on lifelong IVIG therapy, he suffered from neurologic deficits and progressive lung disease and eventually died of lymphoma. Similarly, recent published cases of XLP1 patients either do not survive initial childhood manifestations of XLP1 or succumb to complications in mid-adulthood [10, 12, 18, 20–27]. This remains an important point to emphasize during shared decision making with newly diagnosed patients with XLP1 who are eligible for HSCT.



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