Lymphoproliferative syndrome type 3 D81.4

Rare autosomal recessive immunodeficiency syndrome (combined immunodeficiency/CID) caused by mutation in the CD70 gene (602840) on chromosome 19p13. Immunodeficiency is characterized by increased susceptibility of B cells to Epstein-Barr virus (EBV) infections. Ghosh S et al (2020) identified a total of 16 different mutations in CD27 and 8 in CD70, respectively, based on clinical data from 49 patients from 29 families (CD27, n = 33; CD70, n = 16). The majority of patients (90%) were EBV positive at diagnosis, but only about 30% had manifest infectious mononucleosis. Lymphoproliferation and lymphoma were the major clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed hemophagocytic lymphohistiocytosis. 21 patients (43%) developed autoinflammatory features such as uveitis, arthritis, and periodic fever (Ghosh S et al. 2020).

The disorder results from impaired signaling from proliferating B cells to effector T cells, which take over immune surveillance. Heterozygous carriers may be at increased risk for solid tumors (Abolhassani et al. 2017).

Izawa et al. (2017) identified a homozygous nonsense mutation in the CD70 gene (R179X; 602840.0001) in this condition. The mutation found by whole-exome sequencing and confirmed by Sanger sequencing. Cells derived from this patient had normal levels of CD70 mRNA but no detectable CD70 protein. The patient's CD8+ T cells expanded defectively and showed significantly reduced cytotoxic activity against the patient's EBV-infected B cells compared with controls, but this could be restored by transducing the patient's cells with CD70.

Abolhassani et al (2017) identified homozygous mutations in the CD70 gene (c.250delT, 602840.0002 and F186del, 602840.0003) in 4 patients from two unrelated consanguineous families with LPFS3. Analysis of patient cells showed that the mutations either abolished CD70 protein expression or impaired binding to CD27, indicating loss of function. Functional studies demonstrated that the number of CD8+ T cells of patients decreased compared to controls and cytotoxicity against EBV-infected B cells of patients decreased. This behavior indicates impaired activation by EBV-infected B cells. The results suggest that CD70-CD27 interactions play a nonredundant role in T- and B-cell-mediated immunity, and are particularly important for protection against EBV infection.

Early childhood

The phenotype described by Izawa et al. showed great similarities with the phenotype caused by CD27 deficiency (LPFS2; 615122) (Izawa et al. 2017).

Excellent outcomes after hematopoietic stem cell transplantation (HSCT) supported the timely use of this treatment modality in the collective of Ghosh S et al(2020) (n=43), especially in patients presenting with malignant transformation to lymphoma.

Izawa et al (2017) reported on an 8-year-old boy born to consanguineous Egyptian parents with recurrent EBV-induced B-cell proliferative disorders, including Hodgkin lymphoma. He presented with nodular sclerosing Hodgkin lymphoma at 3 years and 8 months of age and achieved a complete response with chemotherapy and radiation. Since the age of 5, he suffered from recurrent fevers, lymphadenopathies, hepatosplenomegaly associated with a high EBV viral load. No other viral or bacterial infections were present. Likewise, no signs of hemophagocytosis. Laboratory tests of immune parameters were essentially normal. CD8+ T cells, NK cells, and memory B cells were decreased. Proliferation of T cells was normal. At the age of 10 years, lymphoproliferative relapse recurred. The patient was successfully treated with hematopoietic stem cell transplantation.

Abolhassani et al (2017) reported 4 patients from two unrelated consanguineous families with LPFS3. The proband in the first family was a 29-year-old Persian woman who had signs of immunodeficiency in childhood. She had a severe varicella infection at age 5 and developed an inflammatory syndrome with arthritis, aphthous ulcers, and posterior uveitis, as well as recurrent upper respiratory tract infections. She later developed a range of symptoms, including restrictive and obstructive pulmonary function, alopecia areata, ventricular ulcers and gastritis, splenomegaly, and lymphadenopathy. At the age of 17, she was diagnosed with Hodgkin's lymphoma of the stomach. She underwent chemotherapy, which resulted in remission. An older brother had viral encephalitis in infancy and was intellectually impaired but had no other clinical symptoms. Laboratory tests in the brother revealed evidence of infection with EBV, cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella. In the second family of Turkish origin, two brothers presented with recurrent infections in the early years of life and developed cervical lymphadenopathy and EBV-associated Hodgkin's lymphoma at about three years of age. Both eventually achieved remission after chemotherapy; the proband's brother had a successful stem cell transplant. Both patients were in remission at ages 16 and 8 years, respectively. Laboratory tests showed variable hypogammaglobulinemia and poor antibody responses in all patients. The percentage of memory T and B cells was decreased; NK cells were decreased in some patients. All patients required intravenous Ig treatments. Family history indicated that none of the parents had immunodeficiency, but three of the four parents developed solid tumor disease in middle age. The grandparents in the Persian family also developed cancer later in life.

1. Abolhassani H et al. (2017) Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med 214: 91-106.
2. Ghosh S et al (2020) Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency. Blood 136:2638-2655.
3. Izawa K et al (2017) Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J Exp Med 214: 73-89.