Lymphoproliferative syndrome-1 is an autosomal recessive primary immunodeficiency characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinemia. Autoimmune disorders, such as autoimmune hemolytic anemia ... Lymphoproliferative syndrome-1 is an autosomal recessive primary immunodeficiency characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinemia. Autoimmune disorders, such as autoimmune hemolytic anemia or renal disease, may also occur. Patients show a high EBV viral load and decreased invariant natural killer T cells. It is unknown whether patients with ITK mutations are intrinsically susceptible to development of lymphoma or dysgammaglobulinemia in the absence of EBV infection (summary by Stepensky et al., 2011; Linka et al., 2012). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).
Huck et al. (2009) reported 2 sisters, born of consanguineous Turkish parents, who died in childhood after developing severe immune dysregulation and therapy-resistant Epstein-Barr virus (EBV)-positive B-cell proliferation following EBV infection. The older girl presented at age 5 ... Huck et al. (2009) reported 2 sisters, born of consanguineous Turkish parents, who died in childhood after developing severe immune dysregulation and therapy-resistant Epstein-Barr virus (EBV)-positive B-cell proliferation following EBV infection. The older girl presented at age 5 years with aphthous stomatitis and subsequent candida stomatitis. From the age of 6 years, she successively developed recurrent episodes of fever and elevated C-reactive protein (CRP; 123260), nodular interstitial pulmonary infiltrates, generalized lymphadenopathy, hepatosplenomegaly with impaired liver function, pleural and pericardial effusion, anemia, thrombocytopenia, and hypogammaglobulinemia. Laboratory studies were consistent with chronic active EBV infection. Lymph node biopsy showed polymorphic B-cell proliferation. At age 8 years, she developed an EBV-associated Hodgkin lymphoma of the nasal concha. Bone marrow aspirate was normal, with no evidence of lymphoma infiltration, histiocytosis, or hemophagocytosis. Despite treatment, she died of bacterial pneumonia at age 10 years. Her younger sister developed recurrent episodes of fever unresponsive to antibiotic treatment at age 5 years. Within 4 months, the symptoms progressed to a life-threatening condition with profound pancytopenia, retroperitoneal and abdominal lymphadenopathy, hepatosplenomegaly, severely impaired liver function, ascites, and pleural effusion. She had active EBV infection and B-cell lymphoproliferation. She died from complications of a peripheral blood stem cell transplantation. One of the patients examined had decreased numbers of natural killer (NK) T cells. Huck et al. (2009) noted the phenotypic similarities to the X-linked lymphoproliferative syndromes observed in boys. Stepensky et al. (2011) reported a consanguineous Arab family in which 3 patients presented between ages 3 and 5 years with fever, lymphadenopathy, and Hodgkin lymphoma associated with EBV infection. One patient was treated with successfully with chemotherapy but later developed fatal hemophagocytic lymphohistiocytosis; the second patient was treated successfully with chemotherapy but later developed autoimmune renal disease and was treated successfully with antiviral therapy; and the third patient underwent successful bone marrow transplant from a donor sib who was heterozygous for the mutation. Linka et al. (2012) reported a patient, born of consanguineous Moroccan parents, who was diagnosed at age 11 years with an EBV-associated B-cell lymphoproliferative disorder. He also had autoimmune hemolytic anemia, thrombocytopenia, and progressive lymphopenia. He died at age 26 years.
By linkage analysis, followed by candidate gene sequencing, Huck et al. (2009) identified a homozygous mutation in the ITK gene (R335W; 186973.0001) in 2 Turkish sisters with fatal EBV-associated lymphoproliferative syndrome.
In 3 members of a ... By linkage analysis, followed by candidate gene sequencing, Huck et al. (2009) identified a homozygous mutation in the ITK gene (R335W; 186973.0001) in 2 Turkish sisters with fatal EBV-associated lymphoproliferative syndrome. In 3 members of a consanguineous Arab family with lymphoproliferative syndrome-1, Stepensky et al. (2011) identified a homozygous truncating mutation in the ITK gene (Y588X; 186973.0002). The mutation, which was found by homozygosity mapping followed by candidate gene sequencing, segregated with the disorder in the family. In a patient, born of consanguineous Moroccan parents, with lymphoproliferative syndrome-1, Linka et al. (2012) identified a homozygous missense mutation in the ITK gene (R29H; 186973.0003). Linka et al. (2012) performed functional studies on cells from the patients reported by Huck et al. (2009), Stepensky et al. (2011), and Linka et al. (2012), and found that all had a reduced calcium signaling response after TCR stimulation and were unable to enhance calcium response in Itk-null mouse cells, consistent with a loss of function. In vitro studies showed that all mutant proteins had reduced half-lives; the R29H mutation impeded membrane targeting of ITK.