X-linked lymphoproliferative disease

INTRODUCTION — X-linked lymphoproliferative disease (XLP; also called Duncan disease) is a rare disorder that was first identified by Purtillo, et al in the Duncan family, in which 6 of 18 males died of lymphoproliferative disease, including fulminant infectious mononucleosis (FIM) and lymphoma [1,2]. It is caused by pathogenic variants in the signaling lymphocyte activation molecule (SLAM) associated protein (SAP) gene [3,4].

XLP is characterized by severe dysregulation of the immune system, often but not always in response to Epstein-Barr virus (EBV) infection. The three most common clinical manifestations are FIM, dysgammaglobulinemia, and lymphoma, usually of B cell origin [5]. Additional presentations include lymphocytic vasculitis, aplastic anemia, and lymphomatoid granulomatosis [6,7].

X-linked inhibitor of apoptosis (XIAP) deficiency was initially considered a form of XLP (XLP type 2 [XLP2]) [8,9]. However, after further characterization of the disorder, it appears that XIAP deficiency may be better classified as X-linked familial hemophagocytic lymphohistiocytosis (HLH) [10,11]. (See 'Differential diagnosis' below and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetics'.)

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of XLP. Other combined immunodeficiencies are discussed separately. (See "Combined immunodeficiencies: An overview".)

EPIDEMIOLOGY — XLP is estimated to affect one to three of every million males [12,13]. However, the disease is probably underreported since males with fatal fulminant infectious mononucleosis (FIM) are not always evaluated for XLP [14]. There is no racial or ethnic predilection [12,13].

A worldwide XLP registry was established in 1980 as a resource for diagnosis, treatment, and research. By 1995, there were 272 males from 80 families registered [15].

Most females who carry heterozygous mutations in the XLP gene, encoding the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), are clinically unaffected. Random inactivation of one of the two X chromosomes during embryogenesis in females, termed "lyonization," usually leaves an adequate number of lymphocytes with active wild-type X chromosomes to prevent phenotypic disease. However, unbalanced or skewed X chromosome inactivation can lead to predominant expression of a mutated SAP allele and, therefore, clinical disease [16]. In addition, any condition associated with loss of an X chromosome (such as in Turner syndrome) or deletion of the part of the X chromosome containing the SAP gene can, in the presence of a mutation-bearing X chromosome, lead to clinical XLP in a female.

GENETICS — XLP (MIM #308240) is caused by mutations in the gene encoding the signaling lymphocyte activation molecule (SLAM) associated protein (SAP; also called Src homology 2 domain protein 1A [SH2D1A] or DSHP) [3,4] in approximately 60 percent of cases in many studies [3,7,17,18], although other studies have found SH2D1A defects in virtually all cases of XLP [5,13].

XLP is inherited in an X-linked recessive manner. De novo mutations are rare. There is a broad spectrum of SAP/SH2D1A mutations that lead to abnormal or absent SAP protein expression, including deletions or insertions, single nucleotide substitutions, and splice-site abnormalities [12,13,17,18]. Mutations can cause early stop codons, leading to nonsense mediated decay of the messenger ribonucleic acid (mRNA) message and absent SAP protein, abnormally truncated SAP protein with altered function, or destabilized protein due to misfolding or alteration of critical conserved motifs [19,20].

An important aspect of genetics concerns the relationship between genetic defects (genotypes) and clinical manifestations (disease phenotypes). There is no consistent correlation between SH2D1A genotypes and phenotypes in XLP, as exemplified by the observation of considerable variability in phenotype within families sharing the same genotype [21].

PATHOGENESIS — The exact mechanisms underlying the clinical features of XLP remain unclear, even though a genetic defect has been identified that causes this syndrome. The clinical manifestations may be related to lack of immune surveillance for or control of Epstein-Barr virus (EBV) or other unidentified antigenic stimuli or due to ineffective T and natural killer (NK) cell interaction with B cells. There is dysfunction of both cellular immunity (cytotoxic T lymphocyte [CTL] and NK cell dysfunction resulting in decreased cytokine production) and humoral immunity (abnormal immunoglobulin levels and abnormal antibody responses to infections and vaccinations) in XLP. EBV infection is particularly prominent in patients with XLP, perhaps because of the B cell tropism of this virus. However, even though clinical manifestations of XLP are often triggered by EBV infection, most immunologic abnormalities seen in this disorder are not dependent upon the presence of, or prior exposure to, EBV.

Signaling lymphocyte activation molecule (SLAM) associated protein (SAP) is expressed in T cells, NK cells, invariant natural killer T (iNKT) cells, and some B cells. SAP binds to the intracellular domains of most members of the SLAM family of receptors, which are immunoglobulin-like receptors [22]. SLAM (CD150) is a costimulatory receptor that triggers T cell activation via a protein tyrosine phosphorylation signal that is dependent upon SAP expression [19,23]. SAP assists in the recruitment of the Src-related protein tyrosine kinase, Fyn, to SLAM and activation of Fyn. XLP-associated mutated SAP protein molecules have significantly decreased binding to SLAM peptides and to Fyn [19].

SAP also interacts with other members of the SLAM family, including CD84, CD229, CD244 (2B4), NTBA (NK, T, and B cell antigen), and CS1 (CD2 subset 1) [24]. These cell surface receptors are adhesion molecules that are located in the immunologic synapse regions formed between T cells and antigen-presenting cells (APCs) and between NK cells and their target cells [22]. SAP regulates these cellular interactions, which are required for normal development and function of the immune system [25]. In addition, SAP plays a role in the development of T cell populations that have innate immune cell features, such as iNKT cells [13,25-27]. iNKT cells are absent in patients with SAP deficiency.

Activation of T cells via the SLAM-SAP signaling pathway can alter the profile of cytokines produced. As an example, interleukin (IL) 10 production by CD4+ T cells is defective in patients with XLP [28]. These T cells do not provide adequate B cell help, which may contribute to the hypogammaglobulinemia and humoral immunodeficiency seen in patients with XLP. Most immunologic abnormalities are not dependent upon the presence of or prior exposure to EBV. In addition, XLP patients are defective in generating a specific T cell subset, T follicular helper (Tfh) cells [29]. Thf cells are antigen-specific CD4+ T cells that are predominantly located in close proximity to follicles and germinal centers of secondary lymphoid organs and express the chemokine receptor, CXCR5. These CCR5+ cells are important in the formation and maintenance of germinal centers and the establishment of memory B cells and plasma cells [30].

The primary immune response in normal individuals infected with EBV is characterized by proliferation of CD8+ CTLs and NK cells [31]. There are at least three potential mechanisms to explain the abnormal response to EBV infection in patients with XLP:

●SAP enhances apoptosis in T and B cells [32]. Apoptosis plays a role in lymphocyte homeostasis and elimination of deoxyribonucleic acid (DNA) damaged cells. This important process constrains T cell expansion during antigen-induced immune responses. A decrease in apoptosis due to deficiency of SAP may underlie the intense, unchecked CD8+ T cell cytotoxicity stimulated by acute EBV infection in patients with XLP [33-35]. Defective apoptosis is due in part to abnormal restimulation-induced cell death (RICD), which is a self-regulatory form of apoptosis independent of EBV infection that is directly linked to the SAP/NTBA signaling pathway and which may constitute a therapeutic target [35-38].

●Another explanation for the increased cytotoxic cellular responses to EBV is that SAP-deficient CD8+ CTLs from patients with XLP manifest a failure to lyse autologous EBV-infected B cells [39]. The lytic machinery normally polarizes to the area where CTLs contact EBV-infected cells, but this does not occur in SAP-deficient CTLs. Other studies have confirmed the impairment of CD8+ T cell response to EBV-transformed B cells [40].

●The receptor 2B4 can activate, costimulate, or inhibit NK cell cytotoxicity, depending upon its interactions with other molecules [26,31,41,42]. SAP normally inhibits interactions between the 2B4 receptor and negative regulatory molecules. Thus, NK cell activation is inhibited by 2B4 when SAP is absent, leading to reduced NK cell lysis of EBV-infected B cells.

CLINICAL MANIFESTATIONS — The average age at presentation, usually triggered by Epstein-Barr virus (EBV) infection, is 2.5 years [3]. Most affected individuals have no apparent disease prior to presentation, despite their immunologic abnormalities that are present prior to EBV infection [15].

The three most common phenotypes of XLP are [12,15]:

●Fulminant infectious mononucleosis (FIM) due to an abnormal immune response to EBV infection (58 percent) (see "Clinical manifestations and treatment of Epstein-Barr virus infection")

●Dysgammaglobulinemia (22 to 31 percent)

●Lymphoproliferative disease, including lymphoma, usually of B cell origin (30 percent)

In a retrospective series of 91 patients with confirmed XLP, the median age of presentation was four years in patients who were EBV positive and three years in those who were EBV negative [43].

It was previously thought that these clinical manifestations of XLP always occurred as a consequence of EBV infection. However, the second and third of these manifestations can occur without prior EBV infection, suggesting that there are other stimuli that can also trigger abnormal immune responses [12,15,22,44]. As examples:

●In one series, 18 of 82 (22 percent) males with XLP and lymphoma had no evidence of prior EBV infection [45].

●Another series of 309 males with XLP from 89 families found that 12 percent developed dysgammaglobulinemia, lymphoproliferative disease, or aplastic anemia, despite having no evidence of EBV infection [21].

●In a previously mentioned report, approximately 35 percent of patients with known EBV status were EBV negative [43]. Dysgammaglobulinemia and lymphoma were the most common disease manifestations among these patients (52 and 25 percent, respectively), while a positive family history for XLP was the most common presenting feature that prompted evaluation and diagnosis of the patient.

Fulminant infectious mononucleosis — FIM is the most common clinical manifestation of XLP and also has the worst prognosis [6,22,43,44,46].

EBV infection causes a dysregulated and exaggerated immune response in patients with XLP, with excessive proliferation of EBV-infected B cells, cytotoxic T lymphocytes (CTLs), and macrophages in various tissues, including hematopoietic organs, liver, brain, and heart. Massive infiltration of these cells into lymphoid and other organs, in combination with abnormal cytokine release, can cause extensive parenchymal damage, including hepatic necrosis and bone marrow failure. Thrombocytopenia, anemia, hepatic dysfunction, and meningoencephalitis are common in patients with FIM. Many patients develop fulminant hepatitis and virus-associated hemophagocytic syndrome (VAHS), also referred to as acquired or secondary hemophagocytic lymphohistiocytosis (HLH). (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Pathophysiology'.)

FIM and HLH are sometimes listed as separate clinical manifestations of XLP. In the context of EBV infection, FIM and HLH are in essence linked entities and cannot reliably be distinguished from each other. Secondary HLH can occur without the presence of FIM if the offending virus (or infectious trigger in the broader sense) is something other than EBV, such as another herpes family virus. HLH without FIM was observed in approximately 21 percent of EBV-negative patients in one series [43].

The minority of patients who survive FIM may have fulminant hepatitis upon reexposure to EBV. They usually also have residual immune dysfunction, such as abnormal immunoglobulin levels (increased immunoglobulin A [IgA] or immunoglobulin M [IgM], decreased immunoglobulin G1 [IgG1] or immunoglobulin G3 [IgG3]) and/or impaired antibody responses, as well as defective natural killer (NK) cell function.

In one series, FIM and HLH were the most common presenting manifestations of XLP (approximately 40 percent), with an additional 6 percent developing FIM/HLH at a later date [43]. In this series, the mortality of FIM/HLH was approximately 65 percent, which is lower than the historically reported mortality of up to 96 percent.

Dysgammaglobulinemia — Dysgammaglobulinemia occurs in approximately one-third of XLP-affected males and has the best prognosis, especially when treated with immune globulin replacement therapy.

In one cohort of 91 patients with XLP, dysgammaglobulinemia was the presenting manifestation in 22 percent, while more than 50 percent demonstrated dysgammaglobulinemia at any given time (enriched in the subpopulation of EBV-negative patients), with a mortality of approximately 5 percent (compared with the previously published mortality of approximately 50 percent) [43]. This percentage of dysgammaglobulinemia in EBV-negative XLP patients is significantly higher than the one-third of patients originally reported and could be related to increased awareness of dysgammaglobulinemia in the context of XLP, as well as the recognition that disease manifestations in XLP do not depend on EBV infection [28,43].

Patients with dysgammaglobulinemia typically have decreased levels of IgG1 and IgG3, whereas levels of IgA and IgM are elevated, possibly secondary to decreased ability to class-switch from IgM to IgG [15,22,47]. Dysgammaglobulinemia can progress over time to include deficiencies of all isotypes of immunoglobulins. Patients often have minimal antibody response to tetanus and diphtheria toxoids after multiple immunization attempts [22]. B and T cell numbers are normal, although abnormalities of B, T, and NK cell function can occur [6,44]. Furthermore, dysgammaglobulinemia can also be reflected in abnormal EBV serology following EBV infection, including persistent IgM positivity and/or lack of IgG positivity to EBV-associated antigens (eg, viral capsid antigen [VCA] and/or EBV nuclear antigen [EBNA]).

Lymphoma — Lymphomas occur in approximately one-third of males with XLP. These are primarily non-Hodgkin type, B cell lymphomas [6,12]. The excessive proliferation of B cells may be due to impaired immune surveillance and elimination by T cells [22]. Lymphomas are often extranodal, with 75 percent occurring in the ileocecal region. They can also occur in the central nervous system, liver, and kidneys. Histologic classes of lymphomas include Burkitt lymphoma (53 percent of all B cell lymphomas), immunoblastic lymphoma, small cleaved or mixed cell lymphoma, and unclassifiable lymphomas [6,48,49].

Lymphoma or lymphoproliferative disease was the presenting manifestation in approximately 14 percent and occurred at any time in approximately 24 percent of cases in an XLP cohort of 91 patients [43]. Of these, 82 percent had B cell non-Hodgkin lymphoma, which was primarily found in the abdomen and cervical regions. Mortality was approximately 8 percent (down from a historical level of approximately 35 percent).

Other manifestations — Additional presentations of XLP include lymphocytic vasculitis, aplastic anemia, and lymphomatoid granulomatosis [6,7,36,50]. These each occur in approximately 3 percent of patients with XLP. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Lymphomatoid granulomatosis'.)

SOMATIC REVERSION — Some patients have milder clinical features, such as isolated dysgammaglobulinemia, and/or have survived Epstein-Barr virus (EBV) infection. In addition, some patients have exceeded the average life expectancy of those with XLP by several decades. This clinical variability, despite the generally accepted lack of genotype-phenotype relationships, suggests that other factors may modify disease manifestations, severity, and prognosis [21].

One possible explanation for these findings is somatic reversion, which occurs in other immunodeficiency disorders as well. Somatic reversion is a spontaneous genetic change in a disease-causing mutation at the level of a single lymphoid precursor cell that reverts the gene back to normal. Reverted cells that showed signaling lymphocyte activation molecule (SLAM) associated protein (SAP) expression and function, indicating a reversion process, were identified in 12 XLP patients from 10 different kindreds [51,52]. Somatic reversion was found exclusively within CD8+ T cells with an effector memory phenotype. The acquired somatic reversion resulted in wild-type nucleotide and amino acid sequences. The reverted CD8+ T cell populations were maintained in vivo over a period of many years, as measured by persistent SAP expression. These revertant, or spontaneously "gene-corrected," CD8+ T cells showed in vitro cytotoxicity against EBV-infected target cells [52].

LABORATORY FINDINGS — Patients with XLP demonstrate vigorous cytotoxic cellular responses, predominantly involving polyclonally activated alloreactive cytotoxic CD8 T cells, during acute Epstein-Barr virus (EBV) infection. Those who survive acute EBV infection usually have extensive immune defects. B and T cell numbers are normal to increased, but function is abnormal. IgG is low, and IgM is often increased. Natural killer (NK) cell activity is reduced. Anemia and thrombocytopenia may also be present.

DIAGNOSIS — Testing for XLP should be performed in all males diagnosed with:

●Common variable immunodeficiency (CVID) or other hypogammaglobulinemia

●Hemophagocytic lymphohistiocytosis (HLH; especially if associated with Epstein-Barr virus [EBV] infection and/or early mortality), severe infectious mononucleosis

●Lymphoma (especially B cell, non-Hodgkin lymphoma affecting extranodal sites)

Males with a family history of known or suspected XLP should also be tested.

Children with suggestive signs and symptoms should be evaluated in consultation with a clinical immunologist familiar with XLP and the other diseases listed in the differential diagnosis. Referral to a pediatric tertiary care center is highly advised.

Genetic testing — Patients are generally first screened for mutations in the SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM) associated protein (SAP). Demonstration of a gene mutation is the gold standard for diagnosing XLP, but gene sequencing may take weeks to complete, and delayed diagnosis of XLP could be detrimental to treatment.

In one series of families with two or more members with clinical XLP, SH2D1A mutations were detected in 97 percent of affected males and 75 percent of obligate carrier females [12,53]. However, SH2D1A mutations were identified in only approximately 60 percent of persons with XLP phenotype and pertinent family history in other studies [3,7,17,18]. These differences in SH2D1A mutation prevalence may be due errors in testing, promoter or regulatory defects of SH2D1A that were not identified, or defects in other genes not identified that cause a similar phenotype.

Tests for protein expression and function — A more rapid assay that detects presence or absence of SAP protein expression via flow cytometry is also available as a screening tool to quickly diagnose cases of XLP in which protein is not expressed [54]. One study showed that flow-cytometric measurement of SAP accurately identified patients with SH2D1A mutations [55]. Flow-cytometric SAP determination can be combined with a functional measurement of 2B4-mediated natural killer (NK) cell killing of EBV-infected cells when SAP expression is reduced but not absent [56]. As mentioned above, 2B4 promotes killing of EBV-infected cells in normal NK cells, whereas 2B4 interaction results in inhibition of NK cell function in SAP-deficient NK cells [41,42]. (See "Flow cytometry for the diagnosis of inborn errors of immunity", section on 'X-linked lymphoproliferative syndrome, types 1 and 2' and 'Pathogenesis' above.)

Other laboratory studies — Certain laboratory studies should be obtained in males with suspected or confirmed XLP as part of the initial evaluation and ongoing monitoring for disease progression:

●General laboratory studies include a complete blood count with differential, kidney and liver profiles, and coagulation studies (prothrombin time/international normalized ratio [PT/INR], partial thromboplastin time [PTT]), fibrinogen, triglycerides, and lactate dehydrogenase (LDH) to monitor for HLH activity and liver involvement. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

●Inflammatory markers, including soluble interleukin (IL) 2 receptor alpha (sIL2R-alpha), ferritin, and C-reactive protein (CRP), can be used to follow disease progression, especially in patients with associated HLH.

●Further laboratory studies include evaluation of NK cell function, enumeration of lymphocyte subpopulations, quantitative immunoglobulin levels, and EBV studies, including qualitative and/or quantitative EBV-polymerase chain reaction (PCR) and EBV serology. The typical finding in XLP is positive IgG and/or IgM titers to EBV viral capsid antigen (VCA) but negative IgG titer to EBV nuclear antigen (EBNA).

●Additional viral studies (eg, PCR tests for adenovirus, cytomegalovirus [CMV], and human herpesvirus-6 [HHV-6]) should be done in males with XLP who are acutely ill or who are definitively diagnosed with XLP but lack evidence of EBV infection.

●Bone marrow biopsy can be performed to confirm hemophagocytosis, evaluate cytopenias, and identify infiltrating marrow infections. It is also performed as part of lymphoma staging.

Prenatal diagnosis — Prenatal testing is possible for pregnancies of females who are heterozygous XLP carriers, and in vitro fertilization with preimplantation genetic testing of embryos may also be available for carriers for whom the disease-causing mutation has been identified.

Carrier testing — Carrier testing is possible in female relatives of a male with a known or suspected XLP genetic mutation [44].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of XLP includes common variable immunodeficiency (CVID), X-linked inhibitor of apoptosis (XIAP) deficiency, hemophagocytic lymphohistiocytosis (HLH), Chediak-Higashi syndrome (CHS), and Griscelli syndrome.

●Common variable immunodeficiency – CVID is defined as reduced IgG and low levels of IgA and/or IgM, with impaired production of specific antibodies and absence of any other defined immunodeficiency. Affected individuals experience frequent infections, often of the respiratory tract, and may also have autoimmune manifestations such as immune-mediated cytopenias or thyroiditis. Females and males are affected in equal proportions [44,57]. Distinguishing between XLP and CVID is important since the treatment and prognosis differ greatly. (See "Treatment and prognosis of common variable immunodeficiency" and 'Dysgammaglobulinemia' above and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults".)

Some patients with dysgammaglobulinemia secondary to XLP are erroneously diagnosed with CVID [57,58]. One study reported a 17-year-old male with a history of multiple infections and hypogammaglobulinemia leading to a diagnosis of CVID [58]. He later developed pancytopenia and died from fulminant infection (without evidence of prior Epstein-Barr virus [EBV] infection). Genetic analysis identified a mutation in SH2D1A. Another study reported two unrelated boys with recurrent respiratory tract infections and dysgammaglobulinemia that led to the diagnosis of CVID [57]. Further reviews of patient and family histories, including multiple male family members who died at young ages in the family of the second boy in this report, raised suspicions for XLP. Genetic testing in both boys showed SH2D1A mutations. (See 'Somatic reversion' above.)

●X-linked inhibitor of apoptosis – XIAP deficiency was initially considered a form of XLP (XLP type 2 [XLP2]) [8-11]. Several similarities between the two diseases were noted in a retrospective analysis of 33 patients with signaling lymphocyte activation molecule (SLAM) associated protein (SAP) deficiency and 30 patients with XIAP deficiency [9]. HLH was the most common clinical manifestation of XIAP deficiency and was usually triggered by EBV infection. In addition, dysgammaglobulinemia (hypogammaglobulinemia) was also observed in patients with XIAP deficiency. However, the disease course in patients with XIAP deficiency appeared less severe than in XLP, with less frequent neurologic involvement and better prognosis. In addition, there was an association between XIAP deficiency and chronic colitis that was not seen with XLP, and lymphoma was not a feature of XIAP deficiency. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetics'.)

●Hemophagocytic lymphohistiocytosis – HLH often occurs in individuals without XLP [59]. There are familial forms of HLH and forms associated with a number of different infections (including EBV), autoimmune disorders, or malignancies. Secondary EBV-associated HLH accounts for approximately one-third of cases of HLH in North America. These cases often present beyond infancy and may be followed by prolonged remission after therapy. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Pathophysiology' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetics'.)

●Chediak-Higashi syndrome – CHS is an autosomal-recessive disorder caused by mutations in the lysosomal trafficking regulator (LYST) gene, also called CHS1, which encodes a protein involved in intracellular vesicle formation. Affected individuals have severe immunodeficiency, partial albinism, giant granules in the cytoplasm of their phagocytes, and platelet dysfunction. Patients who do not die from infection eventually enter a lymphoma-like "accelerated phase" of the disease characterized by massive lymphohistiocytic infiltration of virtually all organ systems and an even more profound immunodeficiency. This phase is thought to be triggered by viral infections, particularly EBV, and is usually lethal. (See "Chediak-Higashi syndrome".)

●Griscelli syndrome type 2 – GS2 is an autosomal-recessive disorder affecting cytotoxic T cells. It is caused by mutations in RAB27A, encoding a small guanosine triphosphate hydrolase (GTPase) that controls vesicle movement within cells. Clinical manifestations include immunodeficiency, HLH (often viral triggered), neurologic abnormalities, and partial albinism. (See "Syndromic immunodeficiencies", section on 'Griscelli syndrome'.)

Other primary immunodeficiency disorders can be complicated by severe EBV-associated illness. Several that seem particularly and/or selectively prone to EBV infection and its complications include interleukin (IL) 2-inducible T cell kinase (ITK) deficiency, magnesium transporter 1 (MAGT1) deficiency, and gain-of-function mutations in phosphatidylinositol 3-kinase, catalytic, delta (PIK3CD) [60-62].

MANAGEMENT — Management of XLP focuses upon three aspects: treatment of acute disease manifestations due to Epstein-Barr virus (EBV) infection and/or hemophagocytic lymphohistiocytosis (HLH), prevention of further sequelae, and curative therapy.

Treatment of acute EBV infection — Treatment with antiviral agents and immune globulin with high anti-Epstein-Barr virus (EBV) titers has been marginally beneficial in the setting of acute EBV infection [63]. An alternative is ablative B cell therapy with rituximab (anti-CD20), which has been used successfully in a few patients to control acute primary EBV infection [26,64,65]. Patients treated with rituximab should be carefully monitored for hypogammaglobulinemia and receive preemptive immune globulin replacement therapy.

In one report, two patients with XLP and acute EBV infection received a rituximab dose of 375 mg/m² [64]. Patient 1 received rituximab on day 1, in addition to intravenous methylprednisone, immune globulin, and ganciclovir. Patient 2 received rituximab on day 5, which was repeated on day 12 due to persistent atypical lymphocytosis. Methylprednisone was administered to suppress the activation of T cells. In both patients, the number of B cells dropped to approximately 1 percent or less of the total number of circulating lymphocytes, and leukocyte-associated EBV DNA in the patients' peripheral blood declined to below the detection limit. No lymphoma was reported in these patients during a two-year follow-up period.

Treatment of HLH — Individuals who develop hemophagocytosis should be promptly treated with hemophagocytic lymphohistiocytosis (HLH) specific therapy to induce remission prior to hematopoietic cell transplantation (HCT) [66]. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Overview and indications for treatment'.)

Treatment of lymphoma — Patients with lymphoma should be treated with standard chemotherapy for the specific type of lymphoma and ideally achieve clinical remission before proceeding to HCT [6].

Preventive therapy — Immune globulin replacement therapy has been used in an attempt to prevent primary infection or acute reactivation of EBV in patients with XLP [63]. However, the effectiveness of such therapy has not been determined, and there are case reports of acute EBV in XLP patients receiving intravenous immune globulin [67]. (See "Immune globulin therapy in inborn errors of immunity".)

Rituximab was shown to prevent severe EBV infection and clinical deterioration prior to allogeneic HCT in EBV-negative individuals [68], and this approach is used in the author's practice.

Preemptive therapy for asymptomatic affected male relatives, in particular siblings in the same household as a symptomatic case, should be considered. The goal is prevention of lethal disease manifestations (eg, fulminant infectious mononucleosis [FIM]) and/or protection from infections that pose a threat to successful outcome of HCT. One option is treating with rituximab in combination with immune globulin replacement therapy as soon as the diagnosis of XLP is suspected (eg, based on flow cytometric measurement of impaired signaling lymphocyte activation molecule [SLAM] associated protein [SAP] expression) or confirmed (based upon gene sequencing), keeping in mind that only HCT provides curative treatment.

Curative therapy — HCT is the only available curative treatment for XLP [43,68-73]. Gene therapy studies are ongoing.

Hematopoietic cell transplantation — HCT is indicated in patients with any of the reported manifestations of XLP, including dysgammaglobulinemia and common variable immunodeficiency (CVID). HCT is also the preferred prevention and treatment strategy for asymptomatic patients with SH2D1A mutations (usually identified because of a family history), as it may provide better overall outcomes, as suggested by a retrospective cohort study [74].

In one large series, 43 patients underwent a total of 46 transplants between 1997 and 2009 [43]. The patients were transplanted at a median age of approximately six years (range 8 months to 19 years). The predominant clinical features were dysgammaglobulinemia (47 percent), HLH (37 percent), and lymphoma (28 percent). Just over 50 percent of patients were EBV positive at the time of HCT. Overall survival was approximately 81 percent, with a higher rate seen if a matched family donor was used (92 percent) and if HLH was not the main clinical manifestation of XLP. Survival after HCT was 50 percent in those with HLH, and all of the patients who died exhibited HLH as their main disease manifestation. Overall survival was similar whether traditional myeloablative or nonmyeloablative (reduced-intensity) conditioning was used, although the majority of patients who died received myeloablative conditioning [43].

Reduced-intensity, nonmyeloablative preparative regimens may offer lower morbidity and mortality than myeloablative regimens in selected cases with high disease burden and/or organ dysfunction and have been used successfully in primary immunodeficiencies [6,75,76]. In one series of 16 patients who underwent HCT after reduced-intensity conditioning, one-year survival estimated by Kaplan-Meier analysis was 80 percent, with long-term survival estimated at 71 percent [77]. Survival was similar for patients with or without a history of HLH prior to HCT. The use of cord blood as a source of stem cells, either from a sibling or from a cord blood bank, has the theoretical advantage of being EBV negative but should be used with caution in EBV-positive patients because no EBV-specific immunity is transferred to the patient [73,78]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Selection of an umbilical cord blood graft for hematopoietic cell transplantation" and "Donor selection for hematopoietic cell transplantation", section on 'Umbilical cord blood donors' and "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells", section on 'Umbilical cord blood'.)

Complications of XLP should be treated prior to HCT to improve clinical status and optimize the chance of success of HCT. Methods to protect individuals from infections should also be implemented to prevent clinical deterioration prior to HCT. These methods include prophylaxis against Pneumocystis jirovecii pneumonia. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)

Gene therapy — Gene therapy is under investigation for XLP, with promising preliminary results in a murine model and in vitro human studies [79,80]. Most symptoms in XLP are due to defective T cell function. Correction of the SAP gene defect in human T cells led to improved in vitro cytotoxicity and T follicular helper (Tfh) cell function and also corrected T cell-dependent humoral function and improved tumor clearance in a murine model [80].

Genetic counseling — Genetic counseling is recommended to provide patients and families with information on the nature of XLP disease, its inheritance, and implications for affected relatives and heterozygous female mutation carriers.

PROGNOSIS — In 1995, the overall survival was reported to be 25 percent [15], and, in 1998, mortality was reported as approximately 70 percent by 10 years of age and 100 percent by 40 years of age without hematopoietic cell transplantation (HCT) [3]. Survival has improved since then with the advent of better treatment options. The two main factors responsible for better survival are HCT and the preemptive use of rituximab and concomitant immune globulin replacement therapy to prevent lethal Epstein-Barr virus (EBV) infection in EBV-naïve patients, such that the previous mortality of approximately 70 percent has changed to approximately 70 percent long-term survival [43].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY

●Pathogenesis – X-linked lymphoproliferative disease (XLP) is a rare disorder characterized by severe dysregulation of the immune system, usually in response to Epstein-Barr virus (EBV) infection. Both cellular and humoral immunity are defective. (See 'Pathogenesis' above.)

●Genetics and classification – XLP is caused by mutations in the signaling lymphocyte activation molecule (SLAM) associated protein (SAP) gene in approximately 60 percent of patients. X-linked inhibitor of apoptosis (XIAP) deficiency was initially designated XLP type 2, but it appears that XIAP deficiency is better classified as X-linked familial hemophagocytic lymphohistiocytosis (HLH). (See 'Genetics' above and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetics'.)

●Clinical presentation – The average age at presentation, usually with EBV infection, is 2.5 years. Most affected persons have no apparent disease prior to presentation. The three most common clinical manifestations are fulminant infectious mononucleosis (FIM), typically complicated by HLH; dysgammaglobulinemia; and lymphoma. (See 'Clinical manifestations' above.)

●Management – Management of XLP focuses upon three aspects: treatment of disease manifestations, prevention of further sequelae, and curative therapy (hematopoietic cell transplantation [HCT]). (See 'Management' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.