Lymphoproliferative syndrome X-linked, 1

Purtilo et al (1974, 1975) reported a kindred named Duncan in which 6 males aged 2 to 19 years died of a lymphoproliferative disorder. The subtle, progressive combined variable immunodeficiency disease was characterized by proliferation of lymphocytes. Infectious mononucleosis occurred during or before the terminal events in at least 3 of 6 boys, with fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, atypical lymphocytosis, and a spectrum of agammaglobulinemia to polyclonal hypergammaglobulinemia.

The hematopoietic organs, viscera, and central nervous system were diffusely infiltrated with lymphocytes, plasma cells, and histiocytes, some of which contained erythrocytes. Two of the 6 male half-siblings had lymphomas of the ileum and central nervous system. The authors suggested that Epstein-Barr virus or other viruses triggered the uncontrolled proliferation of lymphocytes and that the decreased attenuation of T-cell function allowed uncontrolled lymphoproliferation."

Hamilton et al (1980) reported on studies of 59 affected men in 7 unrelated families. Thirty-four patients died of infectious mononucleosis, 8 had fatal infectious mononucleosis with immunoblastic sarcoma, 9 patients developed immunodeficiency after Epstein-Barr virus infection, and 8 developed lymphoma.

Purtilo et al (1982) studied 100 cases of XLP in 25 families and proposed four main interrelated phenotypes: infectious mononucleosis (IM), malignant B-cell lymphoma (ML), aplastic anemia (AA), and hypogammaglobulinemia (HGG). Eighty-one of the patients died; 2 were asymptomatic but had immunodeficiency against EBV; 75 had infectious mononucleosis; 17 from this group had aplastic anemia of whom all died within a week. 9 patients developed malignant B-cell lymphoma. 26 of 35 lymphomas were located in the terminal ileum. Heterozygous mothers of diseased individuals had abnormally elevated titers of antibodies to EBV.

Brandau et al (1999) identified a deletion of exon 1 of the SH2D1A gene (300490.0010) in two brothers with early-onset non-Hodgkin lymphoma but without clinical or laboratory evidence of EBV infection. Additional SH2D1A mutations were detected in two other unrelated patients without evidence of EBV infection; one had non-Hodgkin's lymphoma and dysgammaglobulinemia. The development of dysgammaglobulinemia and lymphoma without evidence of prior EBV infection in 4 patients suggests that EBV, unlike fulminant or fatal infectious mononucleosis, is not associated with these particular phenotypes. No SH2D1A mutations were found in 3 families in which clinical features were suggestive of XLP.

In 9 unrelated patients with X-linked lymphoproliferative syndrome, Coffey et al (1998) identified mutations in the SH2D1A gene (300490.0001-300490.0009).

Hayoz et al. (1988) identified a large Swiss family with XLP that was determined to have a patient with acquired hypogammaglobulinemia associated with mononucleosis syndrome at age 18; the patient died at age 19. In this family, a new mutation had occurred in the F8 gene (300841) causing hemophilia A (306700), so that one female was a carrier of both genes.

Sylla et al (1989) demonstrated linkage of XLP to the marker DXS37, located in Xq25-q26, in a large Swiss family with XLP.

Nichols et al (2005) demonstrated that SH2D1A is a critical regulator of NKT cell ontogeny and that the absence of NKT cells may contribute to the XLP phenotype, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia.

Ma et al (2005) demonstrated that insufficient IL10 production could contribute to hypogammaglobulinemia in XLP.

Prenatal diagnosis: Skare et al (1992) established the diagnosis of XLP prenatally.

Differentially, the

• s. XLP2 (300635), caused by a mutation in the XIAP gene (300079) on chromosome Xp25

as well as the non X-linked lymphoproliferative syndrome 1,2,3:

• s. LPFS1 (613011) caused by a mutation in the ITK gene (186973) on chromosome 5q33
• s. LPFS2 (615122), caused by a mutation in the CD27 gene (186711) on chromosome 12p13
• s. LPFS3 (618261), caused by a mutation in the CD70 gene (TNFSF7; 602840) on chromosome 19p13.

Purtilo et al (1974, 1975) reported a kindred named Duncan in which 6 males aged 2 to 19 years died of a lymphoproliferative disorder. The subtle, progressive combined variable immunodeficiency disease was characterized by proliferation of lymphocytes. Infectious mononucleosis occurred during or before the terminal events in at least 3 of 6 boys, with fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, atypical lymphocytosis, and a spectrum of agammaglobulinemia to polyclonal hypergammaglobulinemia.

The hematopoietic organs, viscera, and central nervous system were diffusely infiltrated with lymphocytes, plasma cells, and histiocytes, some of which contained erythrocytes. Two of the 6 male half-siblings had lymphomas of the ileum and central nervous system. The authors suggested that Epstein-Barr virus or other viruses triggered the uncontrolled proliferation of lymphocytes and that the decreased attenuation of T-cell function allowed uncontrolled lymphoproliferation."

Hamilton et al (1980) reported on studies of 59 affected men in 7 unrelated families. Thirty-four patients died of infectious mononucleosis, 8 had fatal infectious mononucleosis with immunoblastic sarcoma, 9 patients developed immunodeficiency after Epstein-Barr virus infection, and 8 developed lymphoma.

Purtilo et al (1982) studied 100 cases of XLP in 25 families and proposed four main interrelated phenotypes: infectious mononucleosis (IM), malignant B-cell lymphoma (ML), aplastic anemia (AA), and hypogammaglobulinemia (HGG). Eighty-one of the patients died; 2 were asymptomatic but had immunodeficiency against EBV; 75 had infectious mononucleosis; 17 from this group had aplastic anemia of whom all died within a week. 9 patients developed malignant B-cell lymphoma. 26 of 35 lymphomas were located in the terminal ileum. Heterozygous mothers of diseased individuals had abnormally elevated titers of antibodies to EBV.

Diagnosis. Prenatal diagnosis.

Skare et al (1992) established the diagnosis of XLP prenatally.

Hayoz et al (1988) identified a large Swiss family with XLP in which one patient was determined to have acquired hypogammaglobulinemia associated with mononucleosis syndrome at age 18 years; the patient died at age 19 years. In this family, a new mutation had occurred in the F8 gene (300841) causing hemophilia A (306700), so that one female was a carrier of both genes.

Sylla et al (1989) demonstrated linkage of XLP to the marker DXS37, located in Xq25-q26, in a large Swiss family with XLP.

In 9 unrelated patients with X-linked lymphoproliferative syndrome, Coffey et al (1998) identified mutations in the SH2D1A gene (300490.0001-300490.0009).

Brandau et al (1999) identified a deletion of exon 1 of the SH2D1A gene (300490.0010) in two brothers with early-onset non-Hodgkin's lymphoma but without clinical or laboratory evidence of EBV infection. Additional SH2D1A mutations were detected in two other unrelated patients without evidence of EBV infection; one had non-Hodgkin's lymphoma and dysgammaglobulinemia. The development of dysgammaglobulinemia and lymphoma without evidence of prior EBV infection in 4 patients suggests that EBV, unlike fulminant or fatal infectious mononucleosis, is not associated with these particular phenotypes. No SH2D1A mutations were found in 3 families in which clinical features were suggestive of XLP.

1. Booth C et al (2011) X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 117: 53-62.

2. Brandau O et al (1999) Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). Hum Molec Genet 8: 2407-2413.

3. Coffey AJ et al (1998) Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genet 20: 129-135.
4. Hamilton JK et al (1980) X-linked lymphoproliferative syndrome registry report. J Pediat 96: 669-673.
5. Hayoz D et al (1988) X-linked lymphoproliferative syndrome: identification of a large family in Switzerland. Am J Med 84: 529-534.
6. Linka RM et al (2012) Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases. Leukemia 26: 963-971.
7. Ma CS et al (2006) Selective generation of functional somatically mutated IgM+CD27+, but not Ig isotype-switched, memory B cells in X-linked lymphoproliferative disease. J Clin Invest 116: 322-333.
8. Nichols KE et al (2005) Regulation of NKT cell development by SAP, the protein defective in XLP. Nature Med 11: 340-345.
9. Purtilo DT et al (1978) Epstein-Barr virus in the X-linked recessive lymphoproliferative syndrome. Lancet 311: 798-801.
10. Purtilo DT et al (1975) X-linked recessive progressive combined variable immunodeficiency (Duncan's disease). Lancet 305: 935-941.
11. Purtilo DT et al (1974) Fatal infectious mononucleosis in familial lymphohistiocytosis. (Letter) New Eng J Med 291: 736.
12. Purtilo DT et al (1977) Variable phenotypic expression of an X-linked recessive lymphoproliferative syndrome. New Eng. J Med 297: 1077-1081.
13. Purtilo DT et al (19991) Methods of detection of new families with X-linked lymphoproliferative disease. Cancer Genet Cytogenet 51: 143-153.
14. Skare J et al (1993) Characterization of three overlapping deletions causing X-linked lymphoproliferative disease. Genomics 16: 254-255.
15. Stepensky P et al (2011) IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica 96: 472-476.
16. Sumegi J et al (1999) The molecular genetics of X-linked lymphoproliferative (Duncan's) disease. Cancer J Sci Am 5: 57-62.
17. Sylla BS et al (1989) Multipoint linkage mapping of the Xq25-q26 region in a family affected by the X-linked lymphoproliferative syndrome. Clin Genet 36: 459-462.