Lymphoproliferative Syndrome 3

A number sign (#) is used with this entry because of evidence that lymphoproliferative syndrome-3 (LPFS3) is caused by homozygous mutation in the CD70 gene (602840) on chromosome 19p13.

Description

Lymphoproliferative syndrome-3 (LPFS3) is an autosomal recessive early-onset immunologic disorder characterized by increased susceptibility to Epstein-Barr virus (EBV) infection in B cells, resulting in abnormal B-cell proliferation and increased susceptibility to B-cell malignancies, including Hodgkin lymphoma. Patients usually have hypogammaglobulinemia without lymphopenia, although some subsets of immune cells may be low and some patients may have recurrent infections. The disorder results from impaired signaling from proliferating B cells to effector T cells that provide immune surveillance. There may be an increased risk of solid tumors in heterozygous carriers (summary by Abolhassani et al., 2017).

For a discussion of genetic heterogeneity of lymphoproliferative syndrome, see XLP1 (308240).

Clinical Features

Izawa et al. (2017) reported an 8-year-old boy, born of consanguineous Egyptian parents, with recurrent EBV-induced B-cell proliferative disorders, including Hodgkin lymphoma. He presented at age 3 years 8 months with nodular sclerosing Hodgkin lymphoma and achieved a complete response with chemotherapy and radiation. Since age 4.5 years, he had recurrent fever, lymphadenopathies, and hepatosplenomegaly associated with high viral load of EBV. He had no other viral or bacterial infections and no evidence of hemophagocytosis. Laboratory studies of immune parameters were essentially normal, but there were some decreased levels of certain subsets of cells, including naive CD8+ T cells, NK cells, and memory B cells. T-cell proliferation was normal. The patient had another lymphoproliferative episode at age 10 years, and underwent successful hematopoietic stem cell transplantation. Izawa et al. (2017) noted that the phenotype was similar, if not identical, to that associated with CD27 deficiency (LPFS2; 615122).

Abolhassani et al. (2017) reported 4 patients from 2 unrelated consanguineous families with LPFS3. The proband in the first family was a 29-year-old Persian woman who had evidence of immune dysfunction in childhood. She had severe varicella infection at age 5 years 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 finger clubbing, restrictive and obstructive pulmonary function, alopecia areata, peptic ulcer and gastritis, splenomegaly, and lymphadenopathy. At age 17, she was found to have gastric Hodgkin lymphoma and underwent chemotherapy, with remission. An older brother had viral encephalitis in infancy and had impaired intellectual development, but no other clinical manifestations. Laboratory studies in the brother showed evidence of infection with EBV, cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella. In the second family, of Turkish origin, 2 brothers presented in the first years of life with recurrent infections and developed cervical lymphadenopathy and EBV-associated Hodgkin lymphoma around 3 years of age. Both eventually achieved remission after chemotherapy; the brother of the proband had successful stem cell transplantation. Both patients were in remission at ages 16 and 8 years, respectively. Laboratory studies in all patients showed variable hypogammaglobulinemia and poor antibody responses, and all required intravenous Ig treatment. Overall T and B cell numbers were essentially normal, but proportions of memory T and B cells were decreased, and NK cells were decreased in some patients. Family history revealed that none of the parents had immunodeficiency, but 3 of the 4 parents developed solid cancers in middle age, and the grandparents in the Persian family also developed cancers later in life.

Inheritance

The transmission pattern of LPFS3 in the families reported by Izawa et al. (2017) and Abolhassani et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a boy, born of consanguineous Egyptian parents, with LPFS3, Izawa et al. (2017) identified a homozygous nonsense mutation in the CD70 gene (R179X; 602840.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient-derived cells showed normal amounts of CD70 mRNA, but no detectable protein. Patient CD8+ T cells did not expand properly and showed markedly decreased cytotoxic activity against the patient's EBV-infected B cells compared to controls, but this could be restored by transduction of patient cells with CD70. Further studies showed that the intrinsic cytotoxicity function of CD8+ T cells was preserved, but the lack of CD70 on patient cells interrupted the CD70-CD27 (186711) signaling pathway for effector T cells. In addition, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells, further illustrating that this pathway is important for immune surveillance of activated B cells.

In 4 patients from 2 unrelated consanguineous families with LPFS3, Abolhassani et al. (2017) identified homozygous mutations in the CD70 gene (c.250delT, 602840.0002 and F186del, 602840.0003). Analysis of patient cells showed that the mutations either abolished CD70 protein expression or impaired binding to CD27, consistent with a loss of function. Detailed functional studies showed that patient CD8+ T cells were decreased in number compared to controls and had decreased cytotoxicity against patient EBV-infected B cells, which was caused by impaired activation by EBV-infected B cells rather than by impaired cytotoxicity of the T cells. In addition, patient memory CD8+ T cells showed decreased expression of CD244 (605554) and NKG2D (611817), which are receptors implicated in controlling EBV infection, consistent with the impaired killing of EBV-infected cells. The findings indicated that CD70-CD27 interactions play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.