A genetic analysis of children with Epstein-Barr virus-positive hemophagocytic lymphohistiocytosis and its association with T-helper type 1/T-helper type 2 cytokines
ZHANG Yao, TANG Yong-Min
Pediatric Hematology and Oncology Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310003, China
Abstract Objective To study the effect of genetic variation on the prognosis of children with Epstein-Barr virus (EBV)-positive hemophagocytic lymphohistiocytosis (HLH) and its association with cytokines. Methods A total of 81 EBV-positive HLH children who received the sequencing of related genes were enrolled. According to the results of gene detection, they were divided into a non-mutation group and a mutation group. According to the pattern of gene mutation, the mutation group was further divided into three subgroups:single heterozygous mutation (SHM), double heterozygous mutation (DHM), and homozygous or compound heterozygous mutation (H-CHM). The serum levels of cytokines were measured and their association with HLH gene mutations was analyzed. Results UNC13D gene mutation had the highest frequency (13/46, 28%). The STXBP2 c.575G > A(p.R192H) and UNC13D c.604C > A(p.L202M) mutations (likely pathogenic) were reported for the first time. The mutation group had a significantly higher level of tumor necrosis factor alpha (TNF-α) than the non-mutation group, while it had a significantly lower level of interferon gamma (IFN-γ) than the non-mutation group (P < 0.05). The IL-4 level of the DHM subgroup was higher than that of the non-mutation group, while the IL-4 level of the H-CHM subgroup was lower than that of the DHM group (P < 0.0083). The H-CHM subgroup had a significantly lower 1-year overall survival rate than the non-mutation group, the SHM subgroup, and the DHM subgroup (39%±15% vs 85%±6%/86%±7%/91%±9%, P=0.001). Conclusions There is a significant reduction in IFN-γ level in the mutation group. Children with homozygous or compound heterozygous mutation tend to have poorer prognosis, while other mutations do not have a significant impact on prognosis.
ZHANG Yao,TANG Yong-Min. A genetic analysis of children with Epstein-Barr virus-positive hemophagocytic lymphohistiocytosis and its association with T-helper type 1/T-helper type 2 cytokines[J]. CJCP, 2020, 22(6): 620-625.
ZHANG Yao,TANG Yong-Min. A genetic analysis of children with Epstein-Barr virus-positive hemophagocytic lymphohistiocytosis and its association with T-helper type 1/T-helper type 2 cytokines[J]. CJCP, 2020, 22(6): 620-625.
Xu XJ, Wang HS, Ju XL, et al. Clinical presentation and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in China:a retrospective multicenter study[J]. Pediatr Blood Cancer, 2017, 64(4):e26264.
[3]
Ishii E. Hemophagocytic lymphohistiocytosis in children:pathogenesis and treatment[J]. Front Pediatr, 2016, 4:47.
[4]
Klutts JS, Ford BA, Perez NR, et al. Evidence-based approach for interpretation of Epstein-Barr virus serological patterns[J]. J Clin Microbiol, 2009, 47(10):3204-3210.
[5]
Zhang K, Jordan MB, Marsh RA, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH[J]. Blood, 2011, 118(22):5794-5798.
[6]
Palterer B, Brugnolo F, Sieni E, et al. Neuromyelitis optica, atypical hemophagocytic lymphohistiocytosis and heterozygous perforin A91V mutation[J]. J Neuroimmunol, 2017, 311:10-13.
[7]
Zhang M, Bracaglia C, Prencipe G, et al. A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis[J]. J Immunol, 2016, 196(6):2492-2503.
[8]
Henter JI, Horne A, Aricó M, et al. HLH-2004:diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis[J]. Pediatr Blood Cancer, 2007, 48(2):124-131.
[9]
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5):405-424.
[10]
Tang Y, Xu X, Song H, et al. Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome[J]. Br J Haematol, 2008, 143(1):84-91.
[11]
Meeths M, Entesarian M, Al-Herz W, et al. Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2[J]. Blood, 2010, 116(15):2635-2643.
[12]
Zhao M, Kanegane H, Kobayashi C, et al. Early and rapid detection of X-linked lymphoproliferative syndrome with SH2D1A mutations by flow cytometry[J]. Cytometry B Clin Cytom, 2011, 80(1):8-13.
[13]
Tesi B, Lagerstedt-Robinson K, Chiang SC, et al. Targeted high-throughput sequencing for genetic diagnostics of hemophagocytic lymphohistiocytosis[J]. Genome Med, 2015, 7:130.
[14]
Liu D, Hu X, Jiang X, et al. Characterization of a novel splicing mutation in UNC13D gene through amplicon sequencing:a case report on HLH[J]. BMC Med Genet, 2017, 18(1):135.
[15]
Kobayashi Y, Salih HM, Kajiume T, et al. Successful treatment with liposteroid followed by reduced intensity stem cell transplantation in an infant with perforin deficiency presenting with hemophagocytic lymphohistiocytosis[J]. J Pediatr Hematol Oncol, 2007, 29(3):178-182.
[16]
Rubin TS, Zhang K, Gifford C, et al. Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH[J]. Blood, 2017, 129(22):2993-2999.
[17]
Tothova Z, Berliner N. Hemophagocytic syndrome and critical illness:new insights into diagnosis and management[J]. J Intensive Care Med, 2015, 30(7):401-412.
[18]
Marsh RA, Haddad E. How I treat primary haemophagocytic lymphohistiocytosis[J]. Br J Haematol, 2018, 182(2):185-199.
[19]
Bittremieux W, Tabb DL, Impens F, et al. Quality control in mass spectrometry-based proteomics[J]. Mass Spectrom Rev, 2018, 37(5):697-711.
[20]
Chinn IK, Eckstein OS, Peckham-Gregory EC, et al. Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis[J]. Blood, 2018, 132(1):89-100.