DiagnosisClinical DiagnosisThe 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 mononucleosisHemophagocytic 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 IgAMales with SAP deficiency have 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 testingDetection of EBV-specific IgM antibodiesAtypical lymphocytosis on peripheral blood smear with expansion of CD8 T cellsIn 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, hypofibrinoginemiaInverted CD4:CD8 ratio in peripheral bloodHemophagocytosis on bone marrow biopsy or in other tissues (CSF, lymph node)CytopeniasSplenomegalyElevated plasma levels of soluble IL-2 receptor alphaHypertriglyceridemiaHyperferritinemiaBecause 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 TestingGenes. XLP is known to be caused by mutations in 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 DiseaseView in own windowGene SymbolProportion of all XLPTest MethodMutations DetectedMutation Detection Frequency by Test Method ¹ Test AvailabilityMalesHeterozygous FemalesSH2D1A83%-97% ^{2Sequence analysisSequence variants 3~100% 2, 4 ,5~75% 6, 7ClinicalDeletion/ duplication analysis 8Deletion / duplication of one or more exons or the whole gene 25%XIAP12% 9Sequence analysisSequence variants 3~100% 4, 10, 1185% 7, 11ClinicalDeletion / duplication analysis 8Deletion / duplication of one or more exons or the whole gene 15% 7, 11Research only 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sumegi et al [2000], Rigaud et al [2006]3. 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.4. 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.5. 25% are predicted to have deletion of exon(s) or the entire gene.6. Sequence analysis of the entire coding region and exon/intron boundaries identifies mutations in approximately 75% of obligate carrier females [Stenson et al 2003].7. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.8. 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.9. 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%.10. 15% are predicted to have deletion of exon(s) or the entire gene. 11. Authors [unpublished data] Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo 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) infectionHemophagocytic 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: Sequence analysis of SH2D1AIf deletion of one or more exons or the entire gene is suspected following sequence analysis, deletion/duplication analysis (recommended) If no mutation is identified in SH2D1A, sequence analysis of XIAPIf deletion of one or more exons or the entire gene is suspected following sequence analysis, deletion/duplication analysis (recommended)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: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) DisordersNo other phenotypes are known to be associated with mutations in SH2D1A or XIAP.}

Natural History XLP1The 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, andLymphoproliferative 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)View in own windowPhenotype% of Individuals with XLP1 with This Phenotype Mortality RateHemophagocytic lymphohistiocytosis (HLH)35.2%65.6%Dysgammaglobulinemia50.5%13%Lymphoma 24.2%9%Fulminant infectious mononucleosis9.9%22.2%Other15.4%28.6%From Booth et al [2011]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 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).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: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 be managed accordingly.Other. Less frequent manifestations of XLP1 are aplastic anemia, vasculitis, and lymphoid granulomatosis.XLP2Males 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) View in own windowPhenotype% of Individuals with XLP2 with This Phenotype ^{1Age of Onset (Years)Hemophagocytic lymphohistiocytosis (HLH)83%0-23 years 1Recurrent HLH67%Typically within one year of initial illness 2Splenomegaly85%0-45 years 1Hypogammaglobulinemia30%0-26 years 1Colitis ± liver disease13%4-41 years 11. Combined from series reported to date including Rigaud et al [2006], Marsh et al [2010], Zhao et al [2010], and Pachlopnik Schmid et al [2011] 2. Pachlopnik Schmid et al [2011]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 CorrelationsNo good correlation exists between SH2D1A and XIAP genotype and phenotype in XLP1 or 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].

Differential DiagnosisThe differential diagnosis of X-linked lymphoproliferative disease (XLP) includes the following:Common variable immunodeficiency (CVID). CVID is defined as low serum concentration of two out of three immunoglobulins (IgG, IgA, IgM) and abnormal production of specific antibodies. Symptoms include recurrent infections (especially of the respiratory tract) at any age. CVID has an estimated incidence of one in 50,000 and occurs equally in males and females. 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. To date, lymphoma has not been reported as a complication of XLP2. Chediak-Higashi syndrome is characterized by partial albinism, abnormal platelet function, and severe immunodeficiency. Mutations in CHS1 [Barbosa et al 1996, Nagle et al 1996], encoding a protein involved in intracellular vesicle formation, are causative; mutations in CHS1 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 dysfunctionEvaluation 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 dehydrogenaseIdentification of potential infectious cofactors (especially viral infection or reactivation) that would require specific treatmentTesting to assess immune function including lymphocyte subset analysis (T cell, B cell, NK cell) and serum concentrations of IgG, IgM, and IgAEstablishing the presence or extent of CNS involvement by evaluating the CSF and performing neuroimaging and neuropsychological assessmentEvaluation of inflammatory factors including serum concentrations of ferritin, sIL2Rα, and other cytokinesEvaluation and monitoring of PT, PTT, and fibrinogenGenetics consultationTreatment of ManifestationsIndividuals 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 [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 [unpublished observations]. 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 ManifestationsIt 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.SurveillanceBlood 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 AvoidIndividuals with XLP who come into contact with EBV are at risk until curative treatment with allogeneic HCT has been performed.Evaluation of Relatives at RiskOnce 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 purposesTherapies Under InvestigationSearch 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.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSH2D1AXq25SH2 domain-containing protein 1AResource of Asian Primary Immunodeficiency Diseases (RAPID)
CCHMC - Human Genetics Mutation DatabaseSH2D1AXIAPXq25Baculoviral IAP repeat-containing protein 4XIAP @ LOVD
Resource of Asian Primary Immunodeficiency Diseases (RAPID)
CCHMC - Human Genetics Mutation DatabaseXIAPData 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) View in own window 300079INHIBITOR OF APOPTOSIS, X-LINKED; XIAP 300490SH2 DOMAIN PROTEIN 1A; SH2D1A 300635LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 2; XLP2 308240LYMPHOPROLIFERATIVE SYNDROME, X-LINKED, 1; XLP1SH2D1ANormal allelic variants. SH2D1A has four exons 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 pathologic effect on the SH2D1A protein [Zhang et al, unpublished]. Pathologic allelic variants. More than 70 pathologic 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, 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. XIAP 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 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].