Lymphoproliferative syndrome-2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (summary by ... Lymphoproliferative syndrome-2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (summary by van Montfrans et al., 2012). The phenotype can vary significantly, from asymptomatic borderline-low hypogammaglobulinemia, to a full-blown symptomatic systemic inflammatory response with life-threatening EBV-related complications, including hemophagocytic lymphohistiocytosis, a lymphoproliferative disorder, and malignant lymphoma requiring stem cell transplantation (summary by Salzer et al., 2013). For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).
Van Montfrans et al. (2012) reported a 21-year-old man of Moroccan descent, born of consanguineous parents, with combined immunodeficiency and persistent symptomatic EBV viremia since early childhood. He presented at age 2.5 years with fever, lymphadenopathy, hepatomegaly, and ... Van Montfrans et al. (2012) reported a 21-year-old man of Moroccan descent, born of consanguineous parents, with combined immunodeficiency and persistent symptomatic EBV viremia since early childhood. He presented at age 2.5 years with fever, lymphadenopathy, hepatomegaly, and EBV seroconversion. Immunoglobulins were initially increased, but later decreased severely to levels below normal after about 6 months, when clinical symptoms remitted. Changes in lymphocyte numbers were compatible with viral infection. After 6 months, Ig replacement therapy was initiated, and the patient has had an uneventful medical history since then. Vaccinations were given without complications, he showed normal growth and development, and he did not develop autoimmunity or cancer. However, EBV plasma load was persistently above normal. T-cell proliferation assays showed strongly reduced mitogen- and antigen-specific responses the first 6 months after clinical presentation, and these responses gradually increased to subnormal and normal levels, respectively, during the following year. Immunologic workup showed complete absence of CD27+ on all lymphocytes, despite the presence of normal naive T cells and switched IgG+ and IgA+ B cells. There was a decreased T cell-dependent B-cell response in vivo and in vitro. In vitro studies showed an impaired T-cell proliferative response to mitogens that strongly depend on CD27 (e.g., CD2; 186990), although proliferative responses against a variety of recall antigens could be detected. Autologous EBV-transformed B cells were lysed by the patient's EBV-specific CD8 T cells. However, the frequency of IL2-producing EBV-specific T cells was reduced compared to controls. Overall, the findings suggested that despite normal T-cell differentiation and maturation, the ability to maintain physiologically relevant recall in the CD8+ T-cell population in vivo was deficient. The NK cell compartment was normal. Family history revealed an older brother who presented with EBV-induced lymphadenopathy, fever, hepatosplenomegaly, and uveitis. In this patient, T-cell responses to mitogens and antigens were absent. He eventually developed aplastic anemia and died in childhood. Van Montfrans et al. (2012) noted the phenotypic similarities to combined variable immunodeficiency (CVID; 607594), but suggested that there were distinctive defects in T cell-dependent B-cell function and likely other clinically relevant abnormalities in T-cell function in these patients. Seidel (2012) reported a girl from a Viennese family of Turkish origin who presented at age 17 months with EBV-associated hemophagocytic lymphohistiocytosis syndrome (HLH) 2 months after developing infectious mononucleosis. Clinical features included fever, pancytopenia, organomegaly, and decreased fibrinogen. She had a systemic inflammatory response with a lymphoproliferative disorder (LPD) and hypogammaglobulinemia. Treatment with high-dose steroids resulted in transient stability, but the symptoms returned when steroids were tapered. At this time, patient B lymphocytes were found to lack CD27 surface expression. She had several additional relapses of the lymphoproliferative disorder, which responded well to rituximab (anti-CD20 antibody). Low-range EBV viremia was persistent. Salzer et al. (2013) reported follow-up of the patient reported by Seidel (2012), who was born of consanguineous parents. Invariant NK cells were nearly absent during the fulminant LPD. She had EBV-specific T cells, but CD8+ T cells showed moderate oligoclonality. Two of her sibs were clinically unaffected, but were positive for EBV nuclear antigen, lacked CD27 on B cells, and showed low-normal antibody responses. One of the sibs received prophylactic IV Ig treatment. Salzer et al. (2013) reported 2 consanguineous Lebanese families with LPFS2. In 1 family, a 4-year-old boy presented at age 18 months with EBV-associated lymphoproliferative disease and HLH. Although immunoglobulin levels were normal at first, he later became hypogammaglobulinemic. He received HLH treatment and rituximab, followed by matched unrelated cord blood transplantation. His younger sister was diagnosed with absent CD27 expression and EBV-infection only after CD27 deficiency had been identified in her brother. In the other family, the proband was a 19-year-old boy who presented at age 15 years with EBV-LPD. He responded to rituximab, but EBV-viremia recurred 3 months later. He was hypergammaglobulinemic at diagnosis, but immunoglobulin levels slowly decreased. He had a relapse of EBV-LPD, which progressed into T-cell lymphoma requiring treatment with rituximab and chemotherapy followed by cord blood transplantation. Flow cytometric analysis at relapse revealed absent CD27+ lymphocytes and very low invariant NK cells. Two older sisters died of suspected EBV-driven lymphoma at age 2 and 22 years. CD27 deficiency was established in the sisters retrospectively from Guthrie card DNA.
In 2 brothers, born of consanguineous Moroccan parents, with autosomal EBV-associated immunodeficiency, van Montfrans et al. (2012) identified a homozygous mutation in the CD27 gene (W8X; 186711.0001). Each unaffected parent was heterozygous for the mutation. The CD27 gene ... In 2 brothers, born of consanguineous Moroccan parents, with autosomal EBV-associated immunodeficiency, van Montfrans et al. (2012) identified a homozygous mutation in the CD27 gene (W8X; 186711.0001). Each unaffected parent was heterozygous for the mutation. The CD27 gene was studied because flow cytometric analysis during diagnostic work-up showed absence of CD27 on all patient lymphocytes. CD27 is recognized as a marker for memory B cells and is considered of diagnostic value in patients who have decreased numbers of switched memory B cells. Mutations in other genes known to be associated with EBV susceptibility, including SH2D1A (300490), XIAP (300079), and PRF1 (170280) were excluded. In 8 affected individuals from 3 unrelated families with LPFS2, Salzer et al. (2013) identified the same homozygous mutation in the CD27 gene (C53Y; 186711.0002). The mutation was identified by exome sequencing in 1 family and confirmed by Sanger sequencing in all families.