First Report on Familial Hemophagocytic Lymphohistiocytosis with an Abnormal Immunophenotype and T Cell Monoclonality in Korea

Hemophagocytic lymphohistiocytosis (HLH) can be divided into primary (genetic or familial) and secondary (acquired or reactive) forms. Abnormal immunophenotyping and downregulation of CD5 or CD7 in T cells have been well characterized in EpsteinBarr virus (EBV)-associated HLH [1, 2]. A few studies have also reported abnormal immunophenotyping of T cells in patients with familial HLH (FHL) [1, 3]. Here, we report a case of FHL with immunophenotypically abnormal T cells and monoclonal T cells confirmed by a T-cell receptor (TCR) gene rearrangement test. A 2-month-old infant was referred to our hospital for further evaluation and treatment of persistent fever and thrombocytopenia. Hepatosplenomegaly and petechiae were observed on physical examination. The total leukocyte count was 1.64×10/L, consisting of 65% lymphocytes, with 1% atypical lymphoid cells. The Hb level was 9.1 g/dL, and the platelet count was 20×10/L. Blood chemistry results were as follows: 570 IU/L AST, 454 IU/L ALT, 657 IU/L lactate dehydrogenase (LDH), 11.4 mg/dL total bilirubin, and 147 mg/dL fibrinogen. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) was 15.3 sec (reference range; 12.6-14.9 sec) and 40.3 sec (reference range; 29.1-41.9 sec), respectively. A serological test to detect any underlying viral infection showed (+, positive; −, negative): antiCMV IgG (+), anti-CMV IgM (−), anti-EB-VCA IgG (+), anti-EBVCA IgM (−), EBV-EA (−), and anti-EB-NA IgG (+). The results of a chromosome study were normal (46,XY). Atypical lymphocytes were observed on peripheral blood smear (Fig. 1A). Hemophagocytic histiocytes were observed on bone marrow biopsy (Fig. 1B, C, and D). EBV was not detected by in situ hybridization. We performed mutation analysis of the FHL-related genes UNC13D and PRF1 using DNA isolated from peripheral blood. Sequencing analysis revealed compound heterozygous mutations in UNC13D [c.118-308 C>T (;)754-1G>C] (Fig. 2A and B). These mutations are frequently observed in Korean FHL patients [4]. Immunophenotyping using bone marrow aspirate revealed an abnormal population of CD8 T cells with downregulated levels of CD5 or CD7 (14.61% of total events; Fig. 2C, D, and E). A TCR gene rearrangement study using paraffin-embedded tissue revealed T cell monoclonality [5] (Fig. 2F). The patient was treated with