OBJECTIVE: To explore the genetic basis for a patient with Familial hemophagocytic lymphohistiocytosis (FHL). METHODS: A 35-day-old male infant who was admitted to the Oriental Hospital Affiliated to Xiamen University on August 3, 2021 due to fever for over 7 hours was selected as the study subject. Whole exome sequencing (WES) was carried out for the proband and his parents, and candidate variants were selected based on the clinical phenotypes of the proband and confirmed by Sanger sequencing. RESULTS: WES and Sanger sequencing results revealed that the proband had harbored compound heterozygous c.67_71delinsGCCC and c.65delC variants of the PRF1 gene, which were respectively inherited from his mother and father. The c.67_71delinsGCCC variant was unreported previously. Based on the guidelines of American College of Medical Genetics and Genomics and clinical manifestations, it was classified as pathogenic (PVS1+PM2_Supporting+PM3+PP4). c.65delC was a known pathogenic variant (PVS1+PM2_Supporting+PM3_Strong+PP4). CONCLUSION The compound heterozygous variants of c.67_71delinsGCCC and c.65delC of the PRF1 gene probably underlay the disease in the proband. The identification of the novel variant has expanded the mutational spectrum of the PRF1 gene.
Male ; Female ; Humans ; Lymphohistiocytosis, Hemophagocytic/genetics* ; Genomics ; Mothers ; Mutation ; Phenotype

OBJECTIVE: To analyze the gene polymorphisms of patients with lymphoma-associated hemophagocytic syndrome in Longyan area, Fujian province. METHODS: A total of 125 patients with lymphoma-associated hemophagocytic syndrome in Longyan, Fujian province, admitted to Longyan First Hospital from May 2017 to November 2020 were selected. Peripheral venous blood was collected from all the patients, and the genotypes of perforin 1 (PRF1) and interleukin-10 (IL-10) gene loci were detected by PCR-fluorescence probe method, and the correlation between PRF1 and IL-10 gene polymorphisms and lymphoma-associated hemophagocytic syndrome was analyzed. RESULTS: The mutation frequencies of PRF1 gene loci rs885821 (C>T), rs885822 (C>T), rs1889490 (G>A) in patients with lymphoma-associated hemophagocytic syndrome were 10.40%, 78.8% and 64.4%, respectively. The mutation frequencies of rs1800872 (A>C), rs1800871 (C>T) and rs1800896 (G>A) of IL-10 loci were 56.0%, 45.2% and 77.6%, respectively. CONCLUSION PRF1 and IL-10 gene loci were polymorphic in patients with lymphoma-associated hemophagocytic syndrome in Longyan area, Fujian province. Alleles C and G of PRF1 and IL-10 were risk factors, and alleles T and A were protective factors.
Humans ; Genotype ; Interleukin-10/genetics* ; Lymphohistiocytosis, Hemophagocytic/genetics* ; Lymphoma/genetics* ; Perforin/genetics* ; Polymorphism, Genetic

OBJECTIVES: To study the value of metagenomic next-generation sequencing (mNGS) in detecting intracranial Epstein-Barr virus (EBV) infection in children with hemophagocytic syndrome (HPS) with central nervous system involvement. METHODS: A retrospective analysis was performed for the cerebrospinal fluid mNGS results of 30 HPS children with central nervous system involvement, which were compared with the results of cerebrospinal fluid EBV-DNA detection and serum EBV antibody profile. The change in serum EBV-DNA copy number after treatment was used to evaluate the efficacy of targeted therapy. RESULTS: The positive rate of EBV in cerebrospinal fluid determined by mNGS was significantly higher than that of EBV-DNA in cerebrospinal fluid (100% vs 10%, P<0.001) and had no significant difference from the positive rate of serum EBV antibody profile (100% vs 93%, P>0.05). The median number of sequences determined by mNGS was 2 400, and serum EBV-DNA copy number before treatment was moderately positively correlated with the number of EBV sequences (r_s=0.693, P<0.001). The multiple linear regression analysis showed that the number of sequences determined by mNGS in cerebrospinal fluid increased with the increase in serum EBV-DNA copy number before treatment (P<0.05). CONCLUSIONS EBV-associated HPS often results in EBV-infected viral encephalitis, and mNGS can significantly increase the detection rate of EBV in cerebrospinal fluid, which may help with clinical diagnosis.
Child ; Humans ; Lymphohistiocytosis, Hemophagocytic/genetics* ; Epstein-Barr Virus Infections/complications* ; Herpesvirus 4, Human/genetics* ; Retrospective Studies ; High-Throughput Nucleotide Sequencing ; Central Nervous System

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.
Child ; Cytokines ; Epstein-Barr Virus Infections ; complications ; Genetic Testing ; Herpesvirus 4, Human ; Humans ; Lymphohistiocytosis, Hemophagocytic ; genetics ; Membrane Proteins ; Th1 Cells ; Th2 Cells

Central Nervous System Diseases ; etiology ; Child ; Female ; Humans ; Infant ; Lymphohistiocytosis, Hemophagocytic ; complications ; diagnosis ; genetics ; Magnetic Resonance Imaging ; Male ; Mutation ; Perforin ; genetics

No abstract available.
Asian Continental Ancestry Group/*genetics ; Base Sequence ; Bone Marrow Cells/cytology/pathology ; Cytomegalovirus Infections/diagnosis ; Epstein-Barr Virus Infections/diagnosis ; Female ; Flow Cytometry ; Heterozygote ; Humans ; Infant ; Killer Cells, Natural/cytology/immunology ; Lymphohistiocytosis, Hemophagocytic/*diagnosis/genetics ; Perforin/*genetics ; Phagocytosis ; Polymorphism, Single Nucleotide ; Republic of Korea ; Sequence Analysis, DNA

Child, Preschool ; Humans ; Lymphohistiocytosis, Hemophagocytic ; diagnosis ; genetics ; therapy ; Male

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disease caused by dysregulated immune responses and overwhelming inflammation to infectious or other triggers of the immune system. HLH may be inherited (primary) or may be secondary to any severe infection, malignancy or rheumatologic disease. Clinical progress of HLH is usually rapid and fatal. Early recognition and assessment of potential causes of HLH is critical to improve survival. Urgent treatment is needed for immunosuppression and degradation of the activated antigen. Over the last two decades, research on genetics and pathophysiology of HLH has much improved treatment outcome of the patient. Here, we review recent advances in our understanding of etiology, pathophysiology, diagnosis and treatment of HLH.
Diagnosis ; Genetics ; Humans ; Immune System ; Immunosuppression ; Inflammation ; Lymphohistiocytosis, Hemophagocytic ; Treatment Outcome

We report the first Far Eastern case of a Korean child with familial hemophagocytic lymphohistiocytosis (HLH) caused by a novel syntaxin 11 (STX11) mutation. A 33-month-old boy born to non-consanguineous Korean parents was admitted for intermittent fever lasting one week, pancytopenia, hepatosplenomegaly, and HLH in the bone marrow. Under the impression of HLH, genetic study revealed a novel homozygous missense mutation of STX11: c.650T>C, p.Leu217Pro. Although no large deletion or allele drop was identified, genotype analysis demonstrated that the homozygous c.650T>C may have resulted from the duplication of a maternal (unimaternal) chromosomal region and concurrent loss of the other paternal allele, likely caused by meiotic errors such as two crossover events. A cumulative study of such novel mutations and their effects on specific protein interactions may deepen the understanding of how abnormal STX1 expression results in deficient cytotoxic function.
Alleles ; Amino Acid Sequence ; Asian Continental Ancestry Group/*genetics ; Base Sequence ; Bone Marrow/metabolism ; Child, Preschool ; Comparative Genomic Hybridization ; DNA Mutational Analysis ; Genotype ; Haplotypes ; Homozygote ; Humans ; Lymphohistiocytosis, Hemophagocytic/*genetics/pathology ; Male ; Molecular Sequence Data ; Mutation, Missense ; Pedigree ; Qa-SNARE Proteins/*genetics ; Republic of Korea ; Sequence Alignment

No abstract available.
Bone Marrow/metabolism/pathology ; DNA Mutational Analysis ; Gene Rearrangement, T-Lymphocyte ; Humans ; Immunophenotyping ; Infant ; Lymphohistiocytosis, Hemophagocytic/*diagnosis ; Male ; Membrane Proteins/chemistry/genetics ; Polymorphism, Single-Stranded Conformational ; Republic of Korea ; T-Lymphocytes/immunology/*metabolism