Lymphoproliferative Disease, X-Linked

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

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 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 (XIAP), respectively, also strongly suggests the diagnosis.

Testing

Prior to an encounter with EBV, males with XLP do not show any uniform abnormalities on laboratory testing; however, the following are seen in some individuals:

• Decreased numbers of lymphocyte subsets including decreased T cells, B cells, and NK cells

• Variably decreased NK cell function

• Dysgammaglobulinemia, most frequently manifest by low serum concentration of IgG, with variable serum concentrations of IgM and/or IgA

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

• Positive heterophil antibodies or monospot testing

• EBV detection by polymerase chain reaction (PCR)

• Detection of EBV-specific IgM antibodies

• Atypical lymphocytosis on peripheral blood smear

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. Assessment of SAP expression is clinically available [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 mutation analysis. It is available on a clinical basis [Marsh et al 2009].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. XLP is known to be caused by mutations in the following two genes:

• SH2D1A, encoding SH2 domain protein-containing protein 1A/SLAM-associated protein (SAP); this disorder is sometimes referred to as XLP1.

• XIAP (known formerly as BIRC4), encoding X-linked inhibitor of apoptosis (XIAP; or baculoviral IAP repeat-containing protein 4); this disorder is sometimes referred to as XLP2.

Other loci. Rarely, the underlying genetic defect is not known in individuals with XLP.

Clinical testing

• XLP1 (SH2D1A)
  
  Sequence analysis of the entire coding region and exon/intron boundaries identifies nucleotide substitutions, small deletions, small insertions, small insertions/deletions, and small inversions. PCR-based sequencing can detect mutations in:

  • Approximately 83%-97% of males with XLP who have two or more maternally related family members with XLP phenotypes [Sumegi et al 2000, Rigaud et al 2006].
    
    Note: Exonic and whole gene deletions account for approximately 25% of mutations in families with XLP1. Because males have one X chromosome, the absence of amplification of a region of a gene under stringent laboratory conditions implies that a large deletion or rearrangement is present. Such deletions can be confirmed by deletion analysis (see Table 1).

  • Approximately 75% of obligate carrier females [Stenson et al 2003].
    
    Note: Because females have two X chromosomes, amplification of a region occurs even in the presence of a large deletion because of the contribution of the second X chromosome; thus, PCR-based sequencing does not accurately detect a large deletion in females. Such deletions can be identified by deletion analysis (see Table 1).

• XLP2 (XIAP)

  • Mutations in XIAP are causative in up to 17% of individuals with XLP [Rigaud et al 2006]. Patients may have deletions or missense or nonsense mutations, the majority of which result in an absence of the protein product, XIAP [Rigaud et al 2006, Marsh et al 2009].

Table 1 summarizes molecular genetic testing for this disorder.

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

Gene Symbol/ Locus	Proportion of all XLP	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method		Test Availability
				Affected Males	Carrier Females
SH2D1A	83%-97%	Sequence analysis	Nucleotide substitutions, small deletions/ insertions, small inversions	97% 1	75% 2	Clinical
		Deletion/ duplication analysis 3	Exonic, multiexonic, and whole-gene deletions		~25%
XIAP	17%	Sequence analysis	Nucleotide substitutions, deletions, insertions	Unknown	Unknown	Clinical

1. Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic/whole-gene deletion on the X chromosome in affected males; confirmation requires deletion/duplication testing.

2. Sequence analysis of genomic DNA cannot detect exonic or whole-gene deletions on the X chromosome in carrier females.

3. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including real-time PCR and multiplex ligation-dependent probe amplification

(MLPA) may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming the diagnosis in a proband. Because bone marrow transplantation becomes an option for acutely ill patients if an SH2D1A or XIAP mutation is identified, molecular genetic testing should be used early in the investigation of the following:

• A severe EBV (or other virus) infection in a male child or adolescent

• Hemophagocytic lymphohistiocytosis (HLH) in a young male

• Immunodeficiency involving hypogammaglobulinemia of uncertain etiology in a young male

• Recurrence of a B-cell (typically non-Hodgkin) lymphoma in a young male

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 use of additional blood samples.

(2) If the immediate survival of the affected individual 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:

• Prior identification of the disease-causing mutation in the family

• If an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no mutation is identified, then by deletion analysis to detect exonic, multiexonic or whole gene deletions.

(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.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in SH2D1A or XIAP.

Natural History

Prior to EBV infection, most males with XLP 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].

Median survival overall for individuals with documented XLP1 is age ten years. Survival into adulthood without allogeneic bone marrow transplantation (BMT) (also called hematopoietic cell transplantation [HCT]) is unusual. Thirty-three per cent of the originally described XLP2 cohort died from HLH between ages six months and 40 years [Rigaud et al 2006].

Fulminant infectious mononucleosis/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). Mortality associated with EBV infection in individuals with XLP is higher than 90%.

HLH may also occur in XLP in the absence of EBV infection.

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-third of males with XLP1, hypogammaglobulinemia of one or more immunoglobulin subclasses is diagnosed prior to EBV infection or in rare survivors of EBV infection. Some of these males were previously considered to have common variable immunodeficiency. All lymphoid cell lines can be affected including T cells, B cells, and natural killer (NK) cells. 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).

Males with XLP2 may also manifest with hypogammaglobulinemia in the absence of HLH [Rigaud et al 2006].

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 are common [Gaspar et al 2002].

Thus far, lymphoma has not been described in XLP2.

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:

• Common variable immunodeficiency (CVID) [Nistala et al 2001, Soresina et al 2002, Aghamohammadi et al 2003, Eastwood et al 2004]

• Familial hemophagocytic lymphohistiocytosis (FHL) [Arico et al 2001, Halasa et al 2003]

• Severe EBV-associated illness [Sumazaki et al 2001]

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

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

Genotype-Phenotype Correlations

No good correlation exists between genotype and phenotype in XLP1 or XPL2. Considerable variability in phenotype can be present even within a family [Sumegi et al 2002, Rigaud et al 2006].

Large SH2D1A deletions do not appear to be associated with a more severe phenotype.

Nomenclature

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

• 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 about 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; thus, no evidence exists for a racial or ethnic predilection.

Evaluations Following Initial Diagnosis

To establish the extent of disease 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 neuropsychologic assessment

• Evaluation of inflammatory factors including serum concentrations of ferritin, sIL2Rα, and other cytokines

• Evaluation and monitoring of PT, PTT, and fibrinogen

Treatment of Manifestations

Individuals with XLP who develop fulminant EBV infection/hemophagocytic lymphohistiocytosis often improve with early treatment (e.g., the HLH-2004 protocol) similar to that used in other life-threatening genetic hemophagocytic disorders including familial hemophagocytic lymphohistiocytosis (FHL) [Henter et al 1997], typically consisting of etoposide, steroids, and cyclosporin. Rituximab (anti-CD20 antibody) may also be considered [Milone et al 2005, Lee et al 2006] as well as IVIG.

Allogeneic HCT is the only curative therapy and should be strongly considered in confirmed cases of XLP as early in life as 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].

Hypogammaglobulinemia is treated with IVIG.

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

Prevention of Primary Manifestations

It is recommended that boys with known or suspected XLP receive regular intravenous (IV) IgG replacement therapy every three to four weeks until definitive treatment can be provided even though earlier attempts to prevent EBV infection with the use of IVIG and/or acyclovir prophylaxis have not been completely effective.

HCT is the only curative therapy and should be strongly 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 at least every six months and more frequently if symptoms of infection develop.

Agents/Circumstances to Avoid

Individuals with XLP should avoid contact with EBV until after curative treatment with allogeneic HCT has occurred.

Testing 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 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• The father of an affected male will not have XLP, nor will he be a carrier of a SH2D1A or XIAP mutation.

• In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Female carriers of XLP are asymptomatic and have no immunologic or biochemical markers of the disorder.

• If pedigree analysis reveals that the proband is the only affected family member, the mother may be a carrier or the affected male may have a de novo gene mutation, in which case the mother is not a carrier.

• If a woman has more than one affected son and the disease-causing mutation cannot be detected in DNA extracted from her leukocytes, she has germline mosaicism.

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:

• Prior identification of the disease-causing mutation in the family

• If an affected male is not available for testing, molecular genetic testing first by sequence analysis; if no mutation is identified, customized testing (if available) to detect exonic, multiexonic or whole-gene deletions

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing 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. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

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 (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 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.

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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

SH2D1A

Normal allelic variants. The SH2D1A gene has four exons that span over 25 kb. No normal allelic variants of the SH2D1A gene 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 pathologic effect on the SH2D1A protein [Zhang et al, unpublished].

Pathologic allelic variants. More than 71 pathologic mutations have been identified in the SH2D1A gene. 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 of the mutations 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, 128-amino acid protein, 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. The XIAP gene has six exons 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].

Pathologic allelic variants. Three pathologic mutations in the XIAP gene 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 [Zhang et al, unpublished].

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].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Reading

Revision History

• 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