{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:26:20Z","timestamp":1790983580499,"version":"4.1.0"},"reference-count":42,"publisher":"American Society of Hematology","issue":"5","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2001,9,1]]},"abstract":"<jats:p>X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency caused by a defect in the SH2D1A gene. At least 3 major manifestations characterize its clinical presentation: fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to infection. In some patients with CVID, a defective btk orCD40-L gene has been found, but most often there is no clearly identified etiology. Here, 2 unrelated families in whom male members were affected by CVID were examined for a defect in theXLP gene. In one family previously reported in the literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas female family members showed only elevated serum immunoglobulin A levels. A grandson of one of the brothers died of a severeAspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was excluded genetically, and they were classified as having CVID. The occurrence of FIM in a male cousin of the brothers led to the XLP diagnosis. Because the SH2D1A gene was found altered in both families, these findings indicate that XLP must be considered when more than one male patient with CVID is encountered in the same family, and SH2D1A must be analyzed in all male patients with CVID. Moreover, these data link defects in the SH2D1A gene to abnormal B-lymphocyte development and to dysgammaglobulinemia in female members of families with XLP disease.<\/jats:p>","DOI":"10.1182\/blood.v98.5.1321","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T12:46:47Z","timestamp":1027774007000},"page":"1321-1325","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":92,"title":["Alterations of the X-linked lymphoproliferative disease geneSH2D1A in common variable immunodeficiency syndrome"],"prefix":"10.1182","volume":"98","author":[{"given":"Massimo","family":"Morra","sequence":"first","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olin","family":"Silander","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Calpe","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Choi","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Oettgen","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Myers","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amos","family":"Etzioni","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Buckley","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cox","family":"Terhorst","sequence":"additional","affiliation":[{"name":"From the Division of Immunology, Beth Israel Deaconess Medical Center, and the Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA; the Division of Allergy and Immunology, Department of Pediatrics, Duke University School of Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical Center, B Rappaport School of Medicine, Technion, Haifa, Israel."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021222420579300_B1","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/S0140-6736(75)92004-8","article-title":"X-linked recessive progressive combined variable immunodeficiency (Duncan's disease).","volume":"1","author":"Purtilo","year":"1975","journal-title":"Lancet."},{"key":"2020021222420579300_B2","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1203\/00006450-199510000-00001","article-title":"X-linked lymphoproliferative disease: twenty-five years after the discovery.","volume":"38","author":"Seemayer","year":"1995","journal-title":"Pediatr Res."},{"key":"2020021222420579300_B3","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/S0952-7915(00)00123-0","article-title":"The gene defective in X-linked lymphoproliferative disease controls T cell dependent immune surveillance against Epstein-Barr virus.","volume":"12","author":"Howie","year":"2000","journal-title":"Curr Opin Immunol."},{"key":"2020021222420579300_B4","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S0952-7915(99)80072-7","article-title":"The abnormal gene in X-linked lymphoproliferative syndrome.","volume":"11","author":"Sullivan","year":"1999","journal-title":"Curr Opin Immunol."},{"key":"2020021222420579300_B5","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1146\/annurev.immunol.19.1.657","article-title":"X-linked lymphoproliferative disease, a progressive immunodeficiency.","volume":"19","author":"Morra","year":"2001","journal-title":"Annu Rev Immunol."},{"key":"2020021222420579300_B6","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S0022-3476(80)80735-9","article-title":"X-linked lymphoproliferative syndrome registry report.","volume":"96","author":"Hamilton","year":"1980","journal-title":"J Pediatr."},{"key":"2020021222420579300_B7","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1172\/JCI110932","article-title":"X-linked lymphoproliferative syndrome: natural history of the immunodeficiency.","volume":"71","author":"Sullivan","year":"1983","journal-title":"J Clin Invest."},{"key":"2020021222420579300_B8","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/2424","article-title":"Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene.","volume":"20","author":"Coffey","year":"1998","journal-title":"Nat Genet."},{"key":"2020021222420579300_B9","doi-asserted-by":"crossref","first-page":"13765","DOI":"10.1073\/pnas.95.23.13765","article-title":"Inactivating mutations in an SH2 domain-encoding gene in X-linked lymphoproliferative syndrome.","volume":"95","author":"Nichols","year":"1998","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021222420579300_B10","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/26683","article-title":"The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM.","volume":"395","author":"Sayos","year":"1998","journal-title":"Nature."},{"key":"2020021222420579300_B11","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1007\/s002510000215","article-title":"Genomic organization and characterization of murine SAP: the gene coding for X-linked lymphoproliferative disease.","volume":"51","author":"Wu","year":"2000","journal-title":"Immunogenetics."},{"key":"2020021222420579300_B12","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1002\/1097-0215(20001101)88:3<439::AID-IJC17>3.0.CO;2-#","article-title":"SH2D1A and SLAM expression in human lymphocytes and derived cell lines.","volume":"88","author":"Nagy","year":"2000","journal-title":"Int J Cancer."},{"key":"2020021222420579300_B13","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1093\/intimm\/12.12.1749","article-title":"Potential pathways for regulation of NK and T cell responses: differential X-linked lymphoproliferative syndrome gene product SAP interactions with SLAM and 2B4.","volume":"12","author":"Sayos","year":"2000","journal-title":"Int Immunol."},{"key":"2020021222420579300_B14","doi-asserted-by":"crossref","first-page":"6981","DOI":"10.4049\/jimmunol.162.12.6981","article-title":"Human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP.","volume":"162","author":"Tangye","year":"1999","journal-title":"J Immunol."},{"key":"2020021222420579300_B15","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1182\/blood.V97.12.3867","article-title":"The cell surface receptors Ly-9 and CD84 recruit the XLP gene product SAP.","volume":"97","author":"Sayos","year":"2001","journal-title":"Blood."},{"key":"2020021222420579300_B16","first-page":"2649","article-title":"EAT-2 is a novel SH2 domain containing protein that is up regulated by Ewing's sarcoma EWS\/FLI1 fusion gene.","volume":"13","author":"Thompson","year":"1996","journal-title":"Oncogene."},{"key":"2020021222420579300_B17","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/ajmg.1320400309","article-title":"Immunoglobulin class and subclass deficiencies prior to Epstein-Barr virus infection in males with X-linked lymphoproliferative disease.","volume":"40","author":"Grierson","year":"1991","journal-title":"Am J Med Genet."},{"key":"2020021222420579300_B18","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1046\/j.1365-2141.2000.01884.x","article-title":"Recurrent B-cell non-Hodgkin's lymphoma in two brothers with X-linked lymphoproliferative disease without evidence for Epstein-Barr virus infection.","volume":"108","author":"Strahm","year":"2000","journal-title":"Br J Haematol."},{"key":"2020021222420579300_B19","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/S0167-5699(97)01086-4","article-title":"Common variable immunodeficiency: how many diseases?","volume":"18","author":"Spickett","year":"1997","journal-title":"Immunol Today."},{"key":"2020021222420579300_B20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1006\/clim.1999.4725","article-title":"Common variable immunodeficiency: clinical and immunological features of 248 patients.","volume":"92","author":"Cunningham-Rundles","year":"1999","journal-title":"Clin Immunol."},{"key":"2020021222420579300_B21","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1073\/pnas.91.3.1099","article-title":"CD40 ligand expression is defective in a subset of patients with common variable immunodeficiency.","volume":"91","author":"Farrington","year":"1994","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021222420579300_B22","doi-asserted-by":"crossref","first-page":"9402","DOI":"10.1073\/pnas.91.20.9402","article-title":"A block in both early T lymphocyte and natural killer cell development in transgenic mice with high-copy numbers of the human CD3E gene.","volume":"91","author":"Wang","year":"1994","journal-title":"Proc Natl Acad Sci U S A."},{"key":"2020021222420579300_B23","volume-title":"Laboratory Test Handbook.","author":"Jacobs","year":"1996"},{"key":"2020021222420579300_B24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1203\/00006450-196803000-00002","article-title":"Hereditary alterations in the immune response: coexistence of \u2018agammaglobulinemia,\u2019 acquired hypogammaglobulinemia and selective immunoglobulin deficiency in a sibship.","volume":"2","author":"Buckley","year":"1968","journal-title":"Pediatr Res."},{"key":"2020021222420579300_B25","first-page":"3118","article-title":"Correlation of mutations of the SH2D1A gene and Epstein-Barr virus (EBV) infection with clinical phenotype and outcome in X-linked lymphoproliferative disease (XLP).","volume":"96","author":"Sumegi","year":"2000","journal-title":"Blood."},{"key":"2020021222420579300_B26","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1006\/clim.1999.4799","article-title":"Diagnostic criteria for primary immunodeficiencies.","volume":"93","author":"Conley","year":"1999","journal-title":"Clin Immunol."},{"key":"2020021222420579300_B27","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1006\/clim.2000.4956","article-title":"Mutations in activation-induced cytidine deaminase in patients with hyper IgM syndrome.","volume":"3","author":"Minegish","year":"2000","journal-title":"Clin Immunol."},{"key":"2020021222420579300_B28","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/(SICI)1097-0215(19980529)76:5<694::AID-IJC14>3.0.CO;2-4","article-title":"Epstein-Barr virus-infected B cells of males with the X-linked lymphoproliferative syndrome stimulate and are susceptible to T-cell\u2013mediated lysis.","volume":"76","author":"Jager","year":"1998","journal-title":"Int J Cancer."},{"key":"2020021222420579300_B29","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1126\/science.6158759","article-title":"Deficient natural killer cell activity in X-linked lymphoproliferative syndrome.","volume":"210","author":"Sullivan","year":"1980","journal-title":"Science."},{"key":"2020021222420579300_B30","first-page":"280","article-title":"Studies of EBV-lymphoid cell interactions in two patients with the X-linked lymphoproliferative syndrome: normal EBV-specific HLA-restricted cytotoxicity.","volume":"63","author":"Rousset","year":"1986","journal-title":"Clin Exp Immunol."},{"key":"2020021222420579300_B31","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1084\/jem.192.3.337","article-title":"X-linked lymphoproliferative disease: 2B4 molecules displaying inhibitory rather than activating function killer cells to kill Epstein-Barr virus-infected cells.","volume":"3","author":"Parolini","year":"2000","journal-title":"J Exp Med."},{"key":"2020021222420579300_B32","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.4049\/jimmunol.165.7.3549","article-title":"Defective natural killer cell activation in x-linked lymphoproliferative disease.","volume":"165","author":"Benoit","year":"2000","journal-title":"J Immunol."},{"key":"2020021222420579300_B33","doi-asserted-by":"crossref","first-page":"2932","DOI":"10.4049\/jimmunol.165.6.2932","article-title":"Functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome.","volume":"165","author":"Tangye","year":"2000","journal-title":"J Immunol."},{"key":"2020021222420579300_B34","doi-asserted-by":"crossref","first-page":"180","DOI":"10.7326\/0003-4819-101-2-180","article-title":"Delayed onset of infectious mononucleosis associated with acquired agammaglobulinemia and red cell aplasia.","volume":"101","author":"Purtilo","year":"1984","journal-title":"Ann Intern Med"},{"key":"2020021222420579300_B35","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1006\/smim.2000.0217","article-title":"The CD2-subset of the Ig superfamily of cell surface molecules: receptor-ligand pairs expressed by NK and other immune cells.","volume":"12","author":"Tangye","year":"2000","journal-title":"Semin Immunol."},{"key":"2020021222420579300_B36","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1084\/jem.185.6.993","article-title":"Soluble and membrane-bound forms of signaling lymphocytic activation molecule (SLAM) induce proliferation and Ig synthesis by activated human B lymphocytes.","volume":"185","author":"Punnonen","year":"1997","journal-title":"J Exp Med."},{"key":"2020021222420579300_B37","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1038\/35022579","article-title":"SLAM (CDw150) is a cellular receptor for measles virus.","volume":"406","author":"Tatsuo","year":"2000","journal-title":"Nature."},{"key":"2020021222420579300_B38","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1136\/bmj.2.5758.380","article-title":"Dysgammaglobulinaemia complicated by disseminated measles.","volume":"2","author":"Mawhinney","year":"1971","journal-title":"Br Med J."},{"key":"2020021222420579300_B39","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1542\/peds.39.5.659","article-title":"Pathologic variants of congenital hypogamma-globulinemia: an analysis of 3 patients dying of measles.","volume":"39","author":"Lipsey","year":"1967","journal-title":"Pediatrics."},{"key":"2020021222420579300_B40","doi-asserted-by":"crossref","first-page":"904","DOI":"10.4049\/jimmunol.128.2.904","article-title":"Abnormal anti-Epstein Barr virus antibodies in carriers of the X-linked lymphoproliferative syndrome and in females at risk.","volume":"128","author":"Sakamoto","year":"1982","journal-title":"J Immunol."},{"key":"2020021222420579300_B41","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1086\/301828","article-title":"Mutations in btk in patients with presumed X-linked agammaglobulinemia.","volume":"62","author":"Conley","year":"1998","journal-title":"Am J Hum Genet."},{"key":"2020021222420579300_B42","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1002\/1521-4141(200006)30:6<1691::AID-IMMU1691>3.0.CO;2-K","article-title":"Diagnosis of X-linked lymphoproliferative disease by analysis of SLAM-associated protein expression.","volume":"30","author":"Gilmour","year":"2000","journal-title":"Eur J Immunol."}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/98\/5\/1321\/1676900\/h8170101321.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/98\/5\/1321\/1676900\/h8170101321.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,23]],"date-time":"2023-04-23T20:11:13Z","timestamp":1682280673000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/98\/5\/1321\/106051\/Alterations-of-the-Xlinked-lymphoproliferative"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,9,1]]},"references-count":42,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2001,9,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.v98.5.1321","relation":{},"ISSN":["1528-0020","0006-4971"],"issn-type":[{"value":"1528-0020","type":"electronic"},{"value":"0006-4971","type":"print"}],"subject":[],"published":{"date-parts":[[2001,9,1]]}}}