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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Lymphoproliferative Disease, X-Linked

Synonyms: Duncan Disease, XLPD. Includes: SH2D1A-Related Lymphoproliferative Disease, X-Linked; XIAP-Related Lymphoproliferative Disease, X-Linked

, MD, , MS, , MD, MBA, and , MD.

Author Information
, MD
Professor of Pediatrics Hematology/Oncology, Division of Bone Marrow Transplantation and Immune Deficiency
Immunodeficiency and Histiocytosis Program
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
, MS
Project Manager, Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
, MD, MBA
Associate Professor of Pediatrics, Division of Human Genetics
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
, MD
Assistant Professor of Pediatrics, Division of Bone Marrow Transplantation and Immune Deficiency
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio

Initial Posting: ; Last Update: September 19, 2013.

Summary

Disease characteristics. X-linked lymphoproliferative disease (XLP) is caused by mutations in SH2D1A and XIAP (BIRC4). XLP may also occur in rare instances with no identified underlying genetic cause. The three most commonly recognized phenotypes of SH2D1A-related XLP are hemophagocytic lymphohistiocytosis (HLH) associated with Epstein-Barr virus (EBV) infection (58% of individuals), dysgammaglobulinemia (31%), and lymphoproliferative disorders (malignant lymphoma) (30%). Manifestations of SH2D1A-related XLP, including HLH, can also occur in the absence of EBV. XIAP-related XLP also presents with HLH (often associated with EBV) or dysgammaglobulinemia, but no cases of lymphoma have been described to date. HLH resulting from EBV infection, sometimes referred to as severe infectious mononucleosis, is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Fulminant hepatitis, hepatic necrosis, and profound bone marrow failure are typical, resulting in mortality that is higher than 90%, though prompt recognition of the disorder and aggressive treatment interventions likely improve survival. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The prognosis is improved if affected males are managed with regular intravenous immunoglobulin (IVIG) therapy. The malignant lymphomas are typically high-grade B cell lymphomas, non-Hodgkin type, often extranodal, and in particular involving the intestine.

Diagnosis/testing. XLP is typically suspected based on clinical history and tests of immune function. Diagnosis can be confirmed with molecular genetic testing of SH2D1A and/or XIAP. SH2D1A and XIAP encode SLAM-associated protein (SAP) and baculoviral IAP repeat-containing protein 4 (X-linked inhibitor of apoptosis; XIAP), respectively. Absence of SAP or XIAP strongly supports the diagnosis of XLP as well.

Management. Treatment of manifestations: Treatment of XLP-related HLH is similar to that of other life-threatening genetic hemophagocytic disorders and includes immunosuppressive agents such as steroids and etoposide. Rituximab therapy may also be considered. Hypogammaglobulinemia is treated with IVIG replacement therapy. Lymphoma is treated with standard chemotherapy appropriate to the tumor. Regardless of clinical phenotype, the only curative treatment is allogeneic hematopoietic cell transplantation (HCT), which should be considered in most patients as early as possible.

Prevention of primary manifestations: Boys with known or suspected XLP and hypogammaglobulinemia should receive regular intravenous (IV) IgG replacement therapy every three to four weeks until definitive treatment can be provided.

Surveillance: Blood should be monitored by EBV-PCR for evidence of EBV infection if symptoms of infection develop; blood counts and hepatic profiles should be monitored as needed for early evidence of HLH; IgG levels should be monitored as needed.

Agents/circumstances to avoid: Individuals with XLP who come into contact with EBV are at risk until curative treatment with allogeneic HCT has been performed.

Evaluation of relatives at risk: Molecular genetic testing of at-risk sibs and other relatives for the family-specific mutation facilitates early diagnosis and treatment.

Genetic counseling. XLP is inherited in an X-linked manner. Carrier females have a 50% chance of transmitting the disease-causing mutation in each pregnancy: males who inherit the mutation will be affected; females who inherit the mutation will be carriers. Carrier testing of at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family is known. Because of the possibility of germline mosaicism, it is appropriate to offer prenatal diagnosis to couples who have had a child with XLP if the disease-causing mutation in the proband is known.

Diagnosis

Clinical Diagnosis

The diagnosis of X-linked lymphoproliferative disease (XLP) should be considered in males with any of the following:

  • Fatal or near-fatal Epstein-Barr virus (EBV) infection/severe fulminant infectious mononucleosis
  • Hemophagocytic lymphohistiocytosis (HLH) resulting from EBV or other viral illness (e.g., influenza, CMV, adenovirus, varicella), especially in childhood or adolescence; or HLH without an identifiable trigger
  • Hypogammaglobulinemia or presumptive diagnosis of common variable immunodeficiency (CVID)
  • Lymphoma (generally, B-cell non-Hodgkin lymphoma)
  • Family history of one or more maternally related males with an HLH or an XLP phenotype or diagnosis

The diagnosis of XLP is established in males with a mutation in SH2D1A or XIAP. Absence of the gene protein products (SH2 domain-containing protein 1A [SAP] and baculoviral IAP repeat-containing protein 4 [X-linked inhibitor of apoptosis; XIAP], respectively) also strongly suggests the diagnosis.

Testing

Males with XLP do not show any uniform abnormalities on standard immunologic testing; however, the following may be seen:

  • Variably decreased numbers of lymphocyte subsets including decreased T cells, B cells, and NK cells. HLH may be associated with T cell expansion. (Males with SH2D1A mutations have absent iNK [invariant natural killer] T cells while males with XIAP mutations can have normal or decreased iNKT cell populations [Marsh et al 2009].)
  • Dysgammaglobulinemia, most frequently manifest by low serum concentration of IgG, with variable serum concentrations of IgM and/or IgA
  • In males with SAP deficiency, impaired T cell re-stimulation-induced cell death

Evidence of an acute EBV infection is supported by the following:

  • EBV detection by polymerase chain reaction (PCR; preferred method)
  • Positive heterophil antibodies or monospot testing
  • Detection of EBV-specific IgM antibodies
  • Atypical lymphocytosis on peripheral blood smear with expansion of CD8 T cells

In addition to evidence of EBV infection, specific tests that suggest the diagnosis of HLH/fulminant infectious mononucleosis include the following:

  • Markedly elevated liver transaminases and/or liver dysfunction/coagulopathy, hypofibrinoginemia
  • Inverted CD4:CD8 ratio in peripheral blood
  • Hemophagocytosis on bone marrow biopsy or in other tissues (CSF, lymph node)
  • Cytopenias
  • Splenomegaly
  • Elevated plasma levels of soluble IL-2 receptor alpha
  • Hypertriglyceridemia
  • Hyperferritinemia

Because expression of SH2 domain-containing protein 1A (signaling lymphocyte activation molecule [SLAM]-associated protein, or SAP) detected by flow cytometry is abnormally low or absent in individuals with SH2D1A-related XLP, SAP expression can be used as a rapid screen for XLP in individuals with EBV-induced HLH or other presentations [Tabata et al 2005].

XIAP is absent or abnormally low in most individuals with XIAP-related XLP. Thus, XIAP expression by flow cytometry is a useful adjunct to XIAP molecular genetic testing [Marsh et al 2009].

Molecular Genetic Testing

Genes. XLP is known to be caused by mutations in either of two genes:

  • SH2D1A, encoding SH2 domain protein-containing protein 1A/SLAM-associated protein (SAP); this disorder is sometimes referred to as XLP1.
  • XIAP (also known as BIRC4), encoding baculoviral IAP repeat-containing protein 4 (X-linked inhibitor of apoptosis; XIAP); this disorder is sometimes referred to as XLP2.

Evidence for further locus heterogeneity. Rarely, the underlying genetic defect is not identified in individuals with XLP.

Table 1. Summary of Molecular Genetic Testing Used in X-Linked Lymphoproliferative Disease

Gene 1Proportion of all XLPTest MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
MalesHeterozygous Females
SH2D1A83%-97% 4Sequence analysisSequence variants 5~100% 4, 6, 7~75% 8, 9
Deletion/ duplication analysis 10(Multi)exonic or whole-gene deletion/ duplication25%
XIAP12% 11Sequence analysisSequence variants 5~100% 6, 12, 1385% 9, 12
Deletion/ duplication analysis 10(Multi)exonic or whole-gene deletion/ duplication15% 13

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Sumegi et al [2000], Rigaud et al [2006]

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Lack of amplification by PCRs during sequence analysis can suggest a putative deletion in a male; confirmation may require additional testing by deletion/duplication analysis.

7. 25% are predicted to have deletion of one or more exons or the entire gene.

8. Sequence analysis of the entire coding region and exon/intron boundaries identifies mutations in approximately 75% of obligate carrier females [Stenson et al 2003].

9. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

10. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

11. Filipovich et al [2010]. Note: The incidence of XIAP mutations in males who present with an HLH phenotype (as opposed to an XLP phenotype) is likely less than 10%.

12. 15% are predicted to have deletion of one or more exons or the entire gene.

13. Authors [unpublished data]

Testing Strategy

To confirm/establish the diagnosis in a proband. Because bone marrow transplantation becomes an option for acutely ill males if an SH2D1A or XIAP mutation is identified, molecular genetic testing should be used early in the investigation of a male with the following:

  • A severe EBV (or other virus) infection
  • Hemophagocytic lymphohistiocytosis (HLH)
  • Immunodeficiency involving hypogammaglobulinemia of uncertain etiology
  • Recurrence of a B-cell (typically non-Hodgkin) lymphoma

Molecular genetic testing is performed in the following order:

Note: (1) SAP and XIAP expression by flow cytometry may be used as a screening test prior to molecular genetic testing of SH2D1A or XIAP; however, from a practical standpoint, waiting for results of expression studies may delay molecular genetic testing by several days and may require collection of multiple blood samples. (2) If the immediate survival of the affected male is in question, collection of materials for future characterization of underlying genetic defects is appropriate.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and are not at risk of developing clinical findings related to the disorder. (2) Identification of female carriers requires either of the following:

(3) X-chromosome inactivation studies are not suitable for determining carrier status [Harris et al 1992].

Predictive testing for at-risk asymptomatic family members ideally requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

XLP1

The three most commonly recognized phenotypes of X-linked lymphoproliferative disease caused by SH2D1A mutation (XLP1) are (Table 2):

  • An inappropriate immune response to EBV infection resulting in unusually severe and often fatal infectious mononucleosis or hemophagocytic lymphohistiocytosis (HLH) caused by EBV or other viral infection,
  • Dysgammaglobulinemia, and
  • Lymphoproliferative disorders typically of B-cell origin.

Clinical manifestations of XLP vary even among affected members of the same family. Of note, some males with mutations in SH2D1A are asymptomatic and their long-term prognosis is not known.

Prior to EBV infection, most males with XLP1 appear generally healthy and do not have any characteristic clinical findings. In approximately 12% of males with XLP1, dysgammaglobulinemia precedes EBV infection, resulting in varying degrees of hypogammaglobulinemia and recurrent respiratory infections [Sumegi et al 2000].

Pachlopnik Schmid et al [2011] reported mean age at death for individuals with an SH2D1A mutation as 11 years (range 2-69 years). Approximately 50% of affected males reached adulthood; of this group only one had hematopoietic cell transplantation (HCT). In this study, approximately 25% of surviving males were not receiving treatment; 60% received intravenous immunoglobulin (IVIG) only; and 12% were undergoing therapy for lymphoma. Mortality was related to HLH (70%), lymphoma (12%), myelodysplasia (6%), and complications of HCT (12%).

Table 2. Clinical Phenotypes of SH2D1A-Related XLP (XLP1)

Phenotype% of Individuals with XLP1 with This Phenotype Mortality Rate
Hemophagocytic lymphohistiocytosis (HLH)35.2%65.6%
Dysgammaglobulinemia50.5%13%
Lymphoma 24.2%9%
Fulminant infectious mononucleosis9.9%22.2%
Other15.4%28.6%

Fulminant infectious mononucleosis (FIM)/HLH associated with EBV. The most commonly recognized presentation of XLP is a fatal or near-fatal EBV infection associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages [Gaspar et al 2002]. Affected individuals typically have lymphadenopathy and hepatosplenomegaly with extensive parenchymal damage including fulminant hepatitis, hepatic necrosis, and profound bone marrow failure. Death is generally secondary to liver failure. Hemophagocytosis (phagocytosis identified by microscopy of intact or partially degraded blood cells) in bone marrow and/or CNS may also be seen in association with overwhelming EBV infection. Involvement of other tissues may include spleen ("white pulp" necrosis), heart (mononuclear myocarditis), and kidney (mild interstitial nephritis).

Booth et al [2011] found 65% of persons with XLP to be EBV positive at diagnosis. In this group, the most common presentation of XLP was HLH/FIM, seen in 69% of EBV-positive individuals. In contrast, persons who were EBV negative more typically presented with dysgammaglobulinemia (52%) or lymphoma (25%). HLH in the absence of EBV infection occurred in approximately 21%. The overall mortality rate of approximately 30% did not vary significantly between those who were EBV positive and those who were EBV negative. Mortality was calculated based on whether the patient was alive or deceased at point of data collection. This time span varied between patients from day 0 (presentation) to 148 months post-transplant.

Note: In contrast, EBV infection in individuals who do not have XLP can occur as the well-recognized "infectious mononucleosis" (IM); in young infants, it can pass for a self-limited viral illness. IM may have an acute or insidious onset. Common manifestations are fever, malaise, and pharyngitis typically lasting one to four weeks. Variable lymphadenopathy and splenomegaly may persist for weeks or even months. A truncal macular eruption is observed in approximately 25% of individuals during the first two weeks, during which period the "mono spot" test and EBV IgM titers are found. IgG titers generally develop during the second month and persist for life.

Dysgammaglobulinemia. In approximately one half of males with XLP1, hypogammaglobulinemia of one or more immunoglobulin subclasses is diagnosed prior to EBV infection or in survivors of EBV infection. Some of these males were previously considered to have common variable immunodeficiency. All lymphoid cell lines (including T cells, B cells, and natural killer [NK] cells) can be affected. The natural history of individuals diagnosed with the common variable immunodeficiency (CVID) phenotype and subsequently found to have a mutation in SH2D1A is not well documented at this time. The prognosis for males with this phenotype is more favorable if they are managed with regular IVIG (see Management).

Lymphoproliferative disease (malignant lymphoma). Lymphomas or other lymphoproliferative disease occurs in approximately one third of males with XLP1, some of whom have hypogammaglobulinemia or have survived an initial EBV infection. The lymphomas seen in XLP are typically high-grade B-cell lymphomas, non-Hodgkin type, often extranodal, particularly involving the intestine. Approximately 75% of lymphomas occur in the ileocecal region. Other sites include the central nervous system, liver, and kidney [Harrington et al 1987, Gaspar et al 2002].

The lymphomas can be histologically classified as Burkitt's lymphomas (53% of all B-cell lymphomas), immunoblastic lymphomas (12% of all cases), small cleaved or mixed-cell lymphomas (12%), and unclassifiable lymphomas (5% of all cases) [Harrington et al 1987]. Some but not all B-cell lymphomas express the EBV genome, suggesting that the XLP defect alone predisposes to lymphogenesis.

Lymphomas often develop in childhood and may occur prior to EBV exposure. Remission may follow chemotherapy; however, relapse or development of a second lymphoma or other manifestations of XLP is common [Booth et al 2011].

Common variable immunodeficiency (CVID) and hemophagocytic lymphohistiocytosis (HLH). SH2D1A mutations have been described in individuals with phenotypes that overlap with other immunodeficiencies (see Differential Diagnosis) including:

Males with phenotypes that overlap with other immunodeficiencies and an identified SH2D1A or XIAP mutation should be considered to have XLP and be managed accordingly.

Other. Less frequent manifestations of XLP1 are aplastic anemia, vasculitis, and lymphoid granulomatosis.

XLP2

Males with XIAP deficiency (XLP2) typically present with hemophagocytic lymphohistiocytosis (HLH) (often without EBV infection), recurrent episodes of HLH, splenomegaly, and gastrointestinal disease and may be better described as having an X-linked form of familial hemophagocytic lymphohistiocytosis rather than XLP. To date, neither lymphoproliferative disease [Pachlopnik Schmid et al 2011] nor common variable immunodeficiency (CVID) has been reported in males with XIAP deficiency [Salzer et al 2008]. Of note, some males with mutations in XIAP are asymptomatic and their long-term prognosis is not known.

Pachlopnik Schmid et al [2011] reported mean age at death for males with an XIAP mutation as 16 years (range 1-52 years). Approximately 43% reached adulthood; none of this group had HCT. In this study, approximately 60% of surviving males were not receiving treatment; 12% received IVIG only; 12% were undergoing treatment for colitis; and 18% were undergoing treatment for HLH. Mortality was related to HLH (30%), complications of HCT (30%), colitis (23%), liver failure (8%), and pneumonia (8%).

Table 3. Clinical Phenotypes of XIAP Deficiency (XLP2)

Phenotype% of Individuals with XLP2 with This Phenotype 1Age of Onset
Hemophagocytic lymphohistiocytosis (HLH)83%0-23 years 1
Recurrent HLH67%Typically within 1 year of initial illness 2
Splenomegaly85%0-45 years 1
Hypogammaglobulinemia30%0-26 years 1
Colitis ± liver disease13%4-41 years 1

Hemophagocytic lymphohistiocytosis (HLH) poses a significant risk for mortality to males with XLP2. Thirty-three per cent of the originally described XLP2 cohort died from HLH between ages six months and 40 years [Rigaud et al 2006]. Recurrences of HLH are common, particularly within a year of onset of the initial HLH episode [Pachlopnik Schmid et al 2011].

Colitis, a serious complication of XLP2, has a mortality rate of 60% in symptomatic individuals [Pachlopnik Schmid et al 2011].

Dysgammaglobulinemia. Approximately one third of males with XLP2 have hypogammaglobulinemia of one or more immunoglobulin subclasses which, if untreated, may result in life-threatening infections. The prognosis for males with this phenotype is more favorable if they are managed with regular IVIG (see Management).

Transient hypogammaglobulinemia has been reported in a minority of affected males.

In addition, hypergammaglobulinemia has been reported in two males with XIAP deficiency [Pachlopnik Schmid et al 2011].

Genotype-Phenotype Correlations

No strong correlation exists between SH2D1A and XIAP genotype and phenotype in XLP1 and XPL2, respectively. Considerable variability in phenotype can be present even within a family [Sumegi et al 2002, Rigaud et al 2006, Filipovich et al 2010].

Nomenclature

In the past, the following terms were used to describe XLP1:

  • Epstein-Barr virus infection, familial fatal
  • EBV susceptibility (EBVS)
  • X-linked progressive combined variable immunodeficiency 5
  • Purtilo syndrome
  • Duncan disease

Prevalence

The estimated prevalence of XLP is one per one million males. This may be an underestimate given the severity and often rapidly fatal initial presentation, variable expression, clinical overlap with other immunologic disorders, and lack of a functional assay for diagnosis.

XLP has been reported in families of European, African, Asian, and Middle Eastern descent; no evidence exists for a racial or ethnic predilection.

Differential Diagnosis

See Lymphoproliferative Syndrome: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

The differential diagnosis of X-linked lymphoproliferative disease (XLP) includes the following:

  • Common variable immunodeficiency (CVID) is characterized by humoral immune deficiency with onset after age 24 months and usually in young adulthood, resulting in increased susceptibility to infections and diminished responses to protein and polysaccharide vaccines. The most common infections are sinopulmonary. Overall prevalence is approximately one in 30,000 live births and occurs equally in males and females [Stiehm & Johnston 2005]. The genetic etiology of most CVID is currently unknown. XLP should be considered in males with CVID and hypogammaglobulinemia identified during the first decade of life, particularly in the presence of other symptoms or a positive family history.
  • Hemophagocytic lymphohistiocytosis (HLH) has numerous causes:
    • Familial hemophagocytic lymphohistiocytosis (FHL), a group of rare autosomal recessive disorders, is characterized by excessive immune activation with uncontrolled T-lymphocyte and macrophage activation. Familial HLH may also be triggered by EBV infection. These disorders are lethal in childhood unless treated with bone marrow transplantation. Four genes (PRF1, UNC13D [MUNC13-4], STXBP2, and STX11), representing approximately 60% of the genetic basis of FHL, have been identified to date.
    • Secondary EBV-associated HLH is commonly diagnosed in Asia [Imashuku 2002]; it also accounts for approximately 30% of individuals with HLH identified in North America. Individuals with EBV-associated HLH typically have symptomatic presentation beyond infancy [Filipovich 2001] and may achieve prolonged remission with therapy, thus not requiring curative BMT.
    • Arico et al [2001] found mutations in SH2D1A in four of 25 males (16%) who had previously been diagnosed with HLH, suggesting that XLP should be considered in males presenting with HLH who have no family history of affected females. Similarly, Marsh et al [2010] published a series of young males who presented with HLH and an XIAP mutation, prompting the conclusion that XIAP deficiency may be most appropriately classified as an X-linked form of hemophagocytic lymphohistiocytosis rather than an X-linked lymphoproliferative disorder.
  • Severe EBV-associated illness. Approximately one in 1000 persons infected with EBV develops severe EBV-associated illness. XLP1 and 2 should be considered in males with severe EBV-associated illness who fail to respond to conventional therapies, develop secondary symptoms, or have a family history of severe EBV-associated illness. Aplastic anemia is an uncommon but serious complication of severe EBV-associated illness.
  • Recurrent lymphoma. XLP1 should be suspected in boys treated for lymphoma with standard chemotherapy who develop a second distinct lymphoma (not relapse) after achieving initial remission [Sandlund et al 2013]. To date, lymphoma as a complication of XLP2 has not been reported.
  • Chediak-Higashi syndrome is characterized by partial albinism, abnormal platelet function, and severe immunodeficiency. Mutations in LYST [Barbosa et al 1996, Nagle et al 1996], encoding a protein involved in intracellular vesicle formation, are causative; mutations in LYST result in failure to fuse lysosomes properly with phagosomes. Chediak-Higashi syndrome can be differentiated from XLP based on the presence of huge secretory lysosomes in the neutrophils and lymphocytes and giant melanosomes on skin biopsy. Inheritance is autosomal recessive.
  • Griscelli syndrome type 2 (GS2) is a disorder of cytotoxic T lymphocytes caused by mutations in RAB27A, encoding a small GTPase, which controls the movement of vesicles within cells [Ménasché et al 2002]. GS2 is usually associated with neurologic abnormalities in addition to partial albinism with fair skin and silvery-grey hair. Inheritance is autosomal recessive.
  • ITK deficiency. Mutations in ITK have been reported in association with an autosomal recessive form of lymphoproliferative disease [Huck et al 2009, Stepensky et al 2011]. Presentation has been quite variable in the few individuals reported to date and has included fatal hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, and autoimmune-mediated renal disease, often following EBV infection. In contrast to XLP1, four out of five individuals with ITK deficiency developed Hodgkin disease, as opposed to Burkitt lymphoma.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked lymphoproliferative disease (XLP), the following evaluations are recommended:

  • Physical examination to evaluate for rashes, lymphadenopathy, hepatosplenomegaly, and neurologic dysfunction
  • Evaluation of blood and bone marrow compartments (CBC and BM biopsy)
  • Determination of the extent of liver involvement by measuring serum concentration of transaminases, bilirubin, triglycerides, sodium, and lactate dehydrogenase
  • Identification of potential infectious cofactors (especially viral infection or reactivation) that would require specific treatment
  • Testing to assess immune function including lymphocyte subset analysis (T cell, B cell, NK cell) and serum concentrations of IgG, IgM, and IgA
  • Establishing the presence or extent of CNS involvement by evaluating the CSF and performing neuroimaging and neuropsychological assessment
  • Evaluation of inflammatory factors including serum concentrations of ferritin, sIL2Rα, and other cytokines
  • Evaluation and monitoring of PT, PTT, and fibrinogen
  • Genetics consultation

Treatment of Manifestations

Individuals with XLP who develop fulminant EBV infection/HLH often improve with early treatment (e.g., based on HLH-1994 protocol) similar to that used in other life-threatening genetic hemophagocytic disorders including familial hemophagocytic lymphohistiocytosis (FHL) [Henter et al 1997, Jordan et al 2011], typically consisting of etoposide and steroids. Rituximab (anti-CD20 antibody) [Milone et al 2005, Lee et al 2006] as well as IVIG may also be considered.

Allogeneic HCT is the only curative therapy and should be strongly considered in confirmed cases of XLP1 as early in life as is feasible [Lankester et al 2005]. Successful outcomes have been reported with the use of matched sibling donors and marrow or umbilical cord blood from unrelated donors [Gross et al 1996, Filipovich 2001, Lankester et al 2005]. Overall survival appears to be approximately 80%, regardless of conditioning regimen used. However, survival of affected individuals who received a transplant was increased if they were transplanted prior to an episode of HLH [Booth et al 2011].

The outcomes of allogeneic HCT for males with XLP2 are less certain at this time. Early evidence suggests that reduced-intensity conditioning regimens should be considered due to very poor early experience with myeloablative preparative regimens [Marsh et al 2013].

Hypogammaglobulinemia is treated with IVIG.

Lymphoma associated with XLP1 is treated with the standard chemotherapy appropriate to the tumor diagnosis. Once lymphoma remission is achieved, the individual should quickly proceed to allogeneic HCT.

Colitis associated with XLP2 is treated symptomatically and with immunosuppression similar to that used for irritable bowel disease.

Prevention of Primary Manifestations

It is recommended that boys with known or suspected XLP and hypogammaglobulinemia receive regular intravenous (IV) IgG replacement therapy every three to four weeks until definitive treatment can be provided.

HCT is the only curative therapy and should be considered in children with confirmed XLP as early in life as possible.

Surveillance

Blood should be monitored by EBV-PCR for evidence of EBV infection if symptoms of infection develop.

Blood counts and hepatic profiles should be monitored as needed for early evidence of HLH.

IgG levels should also be monitored as needed.

Agents/Circumstances to Avoid

Individuals with XLP who come into contact with EBV are at risk until curative treatment with allogeneic HCT has been performed.

Evaluation of Relatives at Risk

Once the disease-causing mutation has been identified in a proband, molecular genetic testing of at-risk sibs and other maternal male relatives is appropriate for medical management and for consideration of presymptomatic bone marrow transplantation.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked lymphoproliferative disease (XLP) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to sibs depends on the carrier status of the mother.
  • If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers. Female carriers of XLP are asymptomatic and have no immunologic or biochemical markers of the disorder.
  • Germline mosaicism has been demonstrated [Schuster et al 1993]. Thus, even if the disease-causing mutation has not been identified in DNA extracted from the mother's leukocytes, her offspring are still at increased risk.

Offspring of a proband

  • It is likely that in the near future affected males will live to reproduce following bone marrow transplantation and that the chemotherapy regimen used prior to BMT will not render them infertile.
  • Males will pass the disease-causing mutation to all of their daughters and none of their sons. Female carriers of XLP are asymptomatic and have no immunologic or biochemical markers of the disorder.

Other family members of a proband

  • The proband's other maternal relatives and their offspring may be at risk of being carriers (if female) or of being affected with XLP (if male).
  • The exact risk to the proband's maternal relatives depends on the family relationships.

Carrier Detection

Identification of female carriers requires either of the following:

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers. The usual procedure is to determine the sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~15-18 weeks' gestation). If the karyotype is 46,XY and if the SH2D1A or XIAP disease-causing mutation has been identified in a family member, DNA from fetal cells can be analyzed for the known disease-causing mutation.

In pregnancies where the fetus is found to be unaffected, prenatal identification of an HLA-matched potential stem cell donor for an affected sibling may be considered.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Immune Deficiency Foundation (IDF)
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204
    Phone: 800-296-4433 (toll-free)
    Email: idf@primaryimmune.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Lymphoproliferative Disease, X-Linked: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Lymphoproliferative Disease, X-Linked (View All in OMIM)

300079INHIBITOR OF APOPTOSIS, X-LINKED; XIAP
300490SH2 DOMAIN PROTEIN 1A; SH2D1A
300635LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2; XLP2
308240LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1; XLP1

SH2D1A

Normal allelic variants. SH2D1A has four exons (NM_002351.4) that span over 25 kb. No normal allelic variants of SH2D1A are associated with a change in the amino acid sequence of this protein. Population studies of DNA from 50 normal females from southern Ohio identified 11 variants in the intronic sequence, but these are highly unlikely to have any pathogenic effect on the SH2D1A protein [Zhang et al, unpublished].

Pathogenic allelic variants. More than 70 pathogenic mutations have been identified in SH2D1A. Mutations have been found in all four exons. Mutations include deletions and insertions that lead to absence of a functional protein, mutations that interfere with transcription and splicing, nonsense mutations that lead to protein truncation, and missense mutations that affect protein function [Sumegi et al 2002]. One half of these mutations are single-nucleotide substitutions, one quarter are splicing defects or frame shift mutations, and one quarter are large (i.e., exonic, multiexonic, or whole-gene) deletions. These mutations result in improper processing of the SH2D1A message and lead to truncated or unstable protein [Morra et al 2001; Li et al 2003; Stenson et al 2003; Erdõs et al 2005; Zhang et al, unpublished].

Normal gene product. SH2D1A codes for a small, 125-amino acid protein (NP_002342.1), SH2 domain protein 1A (signaling lymphocyte activation molecular [SLAM]-associated protein, or SAP), involved in the intracellular signaling of the SLAM (signaling lymphocyte activation molecule) family of receptors [Veillette 2006, Ma et al 2007].

Abnormal gene product. SH2D1A mutations lead to changes in the amino acid sequence and truncation or absence of SAP, which disrupts binding to SLAM family receptors and resultant signal transduction pathways [Sayos et al 1998, Morra et al 2001]. Loss of functional SAP causes intrinsic defects in lymphocyte function including cytotoxic lymphocyte cytotoxicity, cytokine production by T cells, T cell-dependent humoral immune responses, and development of NKT cells [Veillette 2006, Ma et al 2007]. It is likely that additional functions that could be disturbed by certain mutations of SH2D1A will be defined in the future.

XIAP (BIRC4)

Normal allelic variants. XIAP has seven exons (NM_001167.3) that encode a 497-amino acid protein. About a dozen normal allelic variants are found, most of them deep into the introns and unlikely to affect protein function [Zhang et al, unpublished].

Pathogenic allelic variants. Three pathogenic mutations in XIAP were described in the original cohort of patients with XLP2. Two families were found to have nonsense mutations resulting in early stop codons within exon 1, and the third family was described with a deletion spanning exon 2 [Rigaud et al 2006]. Other mutations, including deletions and nonsense and missense mutations, also occur [Marsh et al 2010, Pachlopnik Schmid et al 2011].

Normal gene product. XIAP encodes for baculoviral IAP repeat-containing protein 4 (X-linked inhibitor of apoptosis; XIAP). As the name implies, XIAP is known to inhibit apoptosis through interaction with caspase-3, -7, and -9. XIAP also has a C-terminal ring finger domain with E3 ubiquitin ligase activity. XIAP is involved in signaling pathways involving nuclear factor-kappa beta, JNK, and TGF-β, and is also involved in intracellular copper homeostasis [Mufti et al 2007].

Abnormal gene product. The majority of XIAP mutations lead to an absence of protein expression [Rigaud et al 2006, Marsh et al 2009]. How this results in the XLP phenotype remains to be definitively explained, but an increased sensitivity of XIAP-deficient lymphocytes to apoptosis and decreased populations of NKT cells have been postulated to contribute to disease pathogenesis [Rigaud et al 2006, Latour 2007, Marsh et al 2009].

References

Published Guidelines/Consensus Statements

  1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 12-3-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. ASHG statement. Professional disclosure of familial genetic information. Available online.1998. Accessed12-3-13. [PMC free article: PMC1376910] [PubMed: 9537923]

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Suggested Reading

  1. Chandrakasan S, Filipovich AH. Hemophagocytic Lymphohistiocytosis: Advances in Pathophysiology, Diagnosis, and Treatment. J Pediatr. 2013;163:1253–9. [PubMed: 23953723]
  2. Rezaei N, Mahmoudi E, Aghamohammadi A, Das R, Nichols K. X-linked lymphoproliferative syndrome: a genetic condition typified by the triad of infection, immunodeficiency and lymphoma. Brit J Haematol. 2010;152:13–30. [PubMed: 21083659]

Chapter Notes

Author History

Alexandra Filipovich, MD (2004-present)
Judith Johnson, MS (2004-present)
Rebecca Marsh, MD (2009-present)
Janos Sumegi, MD, PhD; Cincinnati Children’s Hospital Medical Center (2004-2011)
Kejian Zhang, MD, MBA (2004-present)

Revision History

  • 19 September 2013 (me) Comprehensive update posted live
  • 10 November 2011 (me) Comprehensive update posted live
  • 18 June 2009 (me) Comprehensive update posted live
  • 3 August 2006 (me) Comprehensive update posted to live Web site
  • 27 February 2004 (me) Review posted to live Web site
  • 10 August 2003 (js) Original submission
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