Manifestations of B-cell expansion with NF-κB and T-cell anergy disease overlapping with hemophagocytic lymphohistiocytosis.

ABSTRACT

B cell expansion with NF-κB and T cell anergy (BENTA) is a disease genetically linked with heterozygous gain-of-function (GOF) mutations in the CARD11 gene with an autosomal dominant expression. Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of disorders characterized by systemic inflammation and hypercytokinaemia. Some BENTA patients share similar clinical manifestations as HLH in various aspects, including fever and splenomegaly. In this study, we reported a 15-month-old boy diagnosed as BENTA meeting with diagnostic criteria of HLH. The complications were resolved by antibiotics for controlling severe infection, together with the reduced format of dexamethasone and etoposide for subsiding HLH activities. While the patient was not subjected to disease recurrence and maintained free of infection, a persistent lymphocytosis derived mainly from the expansion of polyclonal B cells was ascertained. Flow cytometry analysis indicated that the subdued degranulation of NK cells prior to treatment had been restored as the HLH-related complications waned. With largely reduced number and ratios in CD4 and CD8 T cells, their proliferation and Vß diversity remained in normal ranges. In vitro stimulation experiment revealed a functional abbreviation of T cells as the percentage of IFNγ-releasing CD3+CD4+ T cells augmented while the percentage reduced in CD3+CD4- T cells. Whole exome sequencing revealed a de novo G123D missense mutation in the CARD11 gene. This new case of BENTA showcased a scenario of predominant HLH activities accompanied by a severe infection normally associated with BENTA. In addition, a brief treatment quenching HLH complication in cooperation with antibiotics for infection control was not able to solve the underlined T cell abnormality as well as B cell expansion caused by CARD11 mutation. A haematopoietic stem cell transplantation or gene therapy is still a pursuit to remedy this inborn error of immunity.