Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report.
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SUBMITTER: Dantas VM
PROVIDER: S-EPMC8264126 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:RationaleFamilial hemophagocytic lymphohistiocytosis (FHL) is a fatal autosomal recessive immunodeficiency disease whose rapid and accurate diagnosis is paramount for appropriate treatment. Mutations in STXBP2 gene have been associated with FHL type 5 (FHL-5). Here, we report the first Tibetan Chinese patient diagnosed with FHL-5 caused by a novel compound heterozygous mutation in STXBP2.Patient concernsA 9-year-old girl who presented with recurrent fever, splenomegaly, pancytopenia, hypofibrinogenemia, and conspicuous bone marrow hemophagocytosis was diagnosed with haemophagocytic lymphohistiocytosis (HLH).DiagnosisFHL mutation analysis of the patient and her parents revealed that she presented compound heterozygosity for STXBP2: a novel missense mutation c.663G > C (p.Glu221Asp) and the known pathogenic splice-site mutation c.1247-1G > C (p.Val417LeufsX126). Bioinformatics analyses predicted that the new mutation was pathogenic and the FHL-5 diagnosis was confirmed.InterventionsUpon diagnosis, HLH-2004-directed chemotherapy was instituted, but there was a relapse. Allogeneic hematopoietic stem cell transplantation (HSCT) was performed.OutcomesAfter transplantation, the patient presented implantation dysfunction, chronic graft-versus-host disease, and 5 episodes of pancreatitis. A follow-up after 5 years revealed that the patient had died of pancreatitis.LessonsThis finding expands the spectrum of FHL-5-related mutations in Chinese patients and indicates a clear genotype-phenotype correlation of FHL-5 in China.
| S-EPMC6824734 | biostudies-literature
Project description:BackgroundFamilial hemophagocytic lymphohistiocytosis (FHL) is a primary immunodefici-ency disease caused by gene defects. The onset of FHL in adolescents and adults may lead clinicians to ignore or even misdiagnose the disease. To the best of our knowledge, this is the first report to detail the clinical features of type 2 FHL (FHL2) with compound heterozygous perforin (PRF1) defects involving the c.163C>T mutation, in addition to correlation analysis and a literature review.Case summaryWe report a case of a 27-year-old male patient with FHL2, who was admitted with a persistent fever and pancytopenia. Through next-generation sequencing technology of hemophagocytic lymphohistiocytosis (HLH)-related genes, we found compound heterozygous mutations of PRF1: c.65delC (p.Pro22Argfs*29) (frameshift mutation, paternal) and c.163C>T (p.Arg55Cys) (missense mutation, maternal). Although he did not receive hematopoietic stem cell transplantation, the patient achieved complete remission after receiving HLH-2004 treatment protocol. To date, the patient has stopped taking drugs for 15 mo, is in a stable condition, and is under follow-up observation.ConclusionThe delayed onset of FHL2 may be related to the PRF1 mutation type, pathogenic variation pattern, triggering factors, and the temperature sensitivity of some PRF1 mutations. For individual, the detailed reason for the delay in the onset of FHL warrants further investigation.
| S-EPMC8026822 | biostudies-literature
Project description:BACKGROUND:Familial haemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with uncontrolled inflammation; the clinical course usually starts within the first years of life, and is usually fatal unless promptly treated and then cured with haematopoietic stem cell transplant. FHL is caused by genetic mutations resulting in defective cell cytotoxicity; three disease related genes have been identified to date: perforin, Munc13-4 and syntaxin-11. A fourth gene, STXBP2, has been identified very recently as responsible for a defect in Munc18-2 in FHL-5. AIMS:To describe the result of the screening of families with HLH and previously unassigned genetic defects. METHODS:Patients with HLH diagnosed according to current diagnostic criteria, and who lacked mutations in the PRF1, Munc13-4, and STX11 genes were sequenced for mutations in STXBP2. Functional study was performed when material was available. RESULTS:Among the 28 families investigated, 4 (14%) with biallelic STXBP2 mutations were identified. They originated from Italy, England, Kuwait and Pakistan. The p.Pro477Leu resulting from c.1430C>T, and p.Arg405Gln resulting from the single c.1214G>A nucleotide change are known, while we contribute two novel mutations: p.Glu132Ala resulting from c.395A>C, and p.Gly541Ser, resulting from c.1621G>A. The detrimental effect of the p.Gly541Ser mutation was documented biochemically and functionally in NK and CD8 cells. Additional polymorphisms are also described. CONCLUSION:These data expand current knowledge on the genetic heterogeneity of FHL and suggest that patients with FHL5 may have different results in degranulation assays under different conditions.
| S-EPMC4115259 | biostudies-literature
Project description:Background Familial hemophagocytic lymphohistiocytosis (FLH) is an autosomal recessive disorder of immune regulation that leads to a hyperinflammatory syndrome. Fetal onset FHL is extremely rare and is considered to be the most severe form of FHL. Case We report a preterm case of FHL that presented as hydrops fetalis. The infant was treated with a chemotherapy regimen based on the HLH-2004 protocol from the third day of life. However, he had persistent cytopenia and died on the 18th day of life due to bacteremia. The detection of defective perforin expression in the patient's natural killer cells and mutations in the PRF1 gene resulted in a molecular diagnosis of FHL. Conclusion We suggest that early diagnosis and the development of an appropriate immunosuppressive strategy that can induce and maintain remission until hematopoietic stem cell transplantation can be performed are required to improve the outcomes of fetal onset FHL.
| S-EPMC4502624 | biostudies-other
Project description:Familial hemophagocytic lymphohistiocytosis (F-HLH) and Griscelli syndrome type 2 (GS) are life-threatening immunodeficiencies characterized by impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell lytic activity. In the majority of cases, these disorders are caused by biallelic inactivating germline mutations in genes such as RAB27A (GS) and PRF1, UNC13D, STX11, and STXBP2 (F-HLH). Although monoallelic (ie, heterozygous) mutations have been identified in certain patients, the clinical significance and molecular mechanisms by which these mutations influence CTL and NK cell function remain poorly understood. Here, we characterize 2 novel monoallelic hemophagocytic lymphohistiocytosis (HLH)-associated mutations affecting codon 65 of STXPB2, the gene encoding Munc18-2, a member of the SEC/MUNC18 family. Unlike previously described Munc18-2 mutants, Munc18-2(R65Q) and Munc18-2(R65W) retain the ability to interact with and stabilize syntaxin 11. However, presence of Munc18-2(R65Q/W) in patient-derived lymphocytes and forced expression in control CTLs and NK cells diminishes degranulation and cytotoxic activity. Mechanistic studies reveal that mutations affecting R65 hinder membrane fusion in vitro by arresting the late steps of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly. Collectively, these results reveal a direct role for SEC/MUNC18 proteins in promoting SNARE-complex assembly in vivo and suggest that STXBP2 R65 mutations operate in a novel dominant-negative fashion to impair lytic granule fusion and contribute to HLH.
| S-EPMC4351505 | biostudies-literature
Project description:Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, approximately 30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%-40% of the FHL cases and the FHL 1 locus on chromosome 9 for approximately 10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes.
| S-EPMC1274472 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that causes systemic inflammation which can progress to multiorgan failure and death. Symptoms and signs commonly seen in HLH include high fever, hepatosplenomegaly, pancytopenia, and hypertriglyceridemia. This report describes the 8-month clinical course of a 17-year-old male with G6PD deficiency who presented with intermittent high fever of unknown origin for 8 months accompanied by pancytopenia and bilateral lower limb weakness. A pathogenic homozygous missense mutation (c.1081A > T p.(Arg361Trp)) in the PRF1 gene was detected by whole exome sequencing (WES). The brain and the whole spine MRI showed leptomeningeal enhancement at different levels involving both the brain and the spine. Therefore, a diagnosis of familial HLH type 2 with CNS involvement was confirmed. Accordingly, treatment with dexamethasone, cyclosporin, and etoposide in addition to intrathecal methotrexate and hydrocortisone was given. The patient showed a dramatic response with significant neurological improvement of the bilateral lower limb weakness. Genetic analysis has helped the patient's family with appropriate genetic counselling. This case highlights the importance of immediate treatment with immunosuppressants and the high clinical suspicion of physicians regarding HLH in areas where consanguinity is common.
| S-EPMC8731261 | biostudies-literature
Project description:Hemophagocytic lymphohistiocytosis (HLH) are basically a heterogenous group of clinical syndromes, characterised by activation and non-malignant proliferation of benign histiocytes i.e. lymphocytes and macrophages, leading to a cytokine storm that accounts for the fever, organomegaly and multi-organ dysfunction. Two types of HLH are described, either due to known genetic defect (familial HLH/FHL) or due to some acquired cause either infection or rheumatological diseases. Here we present a case of a 3 months old baby, admitted with fever, hepatosplenomegaly and cytopenia and ultimately was diagnosed to be a case of Familial HLH type 3 due to defect in UNC13D gene as a result of compound heterozygous for two nonsense mutation resulting in the Munc13-4 protein defect.
| S-EPMC4925480 | biostudies-literature
Project description:BackgroundHemophagocytic Lymphohistiocytosis (HLH) is a life-threatening immunodeficiency and multi-organ disease that affects people of all ages and ethnic groups. Common symptoms and signs of this disease are high fever, hepatosplenomegaly, and cytopenias. Familial form of HLH disease, which is an autosomal recessive hematological disorder is due to disease-causing mutations in several genes essential for NK and T-cell granule-mediated cytotoxic function. For an effective cytotoxic response from cytotoxic T lymphocyte or NK cell encountering an infected cell or tumor cell, different processes are required, including trafficking, docking, priming, membrane fusion, and entry of cytotoxic granules into the target cell leading to apoptosis. Therefore, genes involved in these steps play important roles in the pathogenesis of HLH disease which include PRF1, UNC13D (MUNC13-4), STX11, and STXBP2 (MUNC18-2).Case presentationHere, we report a novel missense mutation in an 8-year-old boy suffered from hepatosplenomegaly, hepatitis, epilepsy and pancytopenia. The patient was born to a first-cousin parents with no previous documented disease in his parents. To identify mutated gene in the proband, Whole Exome Sequencing (WES) utilizing next generation sequencing was used on an Illumina HiSeq 2000 platform on DNA sample from the patient. Results showed a novel deleterious homozygous missense mutation in PRF1 gene (NM_001083116: exon3: c. 1120 T > G, p.W374G) in the patient and then using Sanger sequencing it was confirmed in the proband and his parents. Since his parents were heterozygous for the identified mutation, autosomal recessive pattern of inheritance was confirmed in the family.ConclusionsOur study identified a rare new pathogenic missense mutation in PRF1 gene in patient with HLH disease and it is the first report of mutation in PRF1 in Iranian patients with this disease.
| S-EPMC5415817 | biostudies-literature
Project description:Neonatal hemophagocytic lymphohistiocytosis (HLH) is a medical emergency that can be associated with significant morbidity and mortality. Often these patients present with familial HLH (f-HLH), which is caused by gene mutations interfering with the cytolytic pathway of cytotoxic T-lymphocytes (CTLs) and natural killer cells. Here we describe a male newborn who met the HLH diagnostic criteria, presented with profound cholestasis, and carried a maternally inherited heterozygous mutation in syntaxin-binding protein-2 [STXBP2, c.568C>T (p.Arg190Cys)] in addition to a severe pathogenic variant in glucose 6-phosphate dehydrogenase [G6PD, hemizygous c.1153T>C (Cys385Arg)]. Although mutations in STXBP2 gene are associated with f-HLH type 5, the clinical and biological relevance of the p.Arg190Cys mutation identified in this patient was uncertain. To assess its role in disease pathogenesis, we performed functional assays and biochemical and microscopic studies. We found that p.Arg190Cys mutation did not alter the expression or subcellular localization of STXBP2 or STX11, neither impaired the STXBP2/STX11 interaction. In contrast, forced expression of the mutated protein into normal CTLs strongly inhibited degranulation and reduced the cytolytic activity outcompeting the effect of endogenous wild-type STXBP2. Interestingly, arginine 190 is located in a structurally conserved region of STXBP2 where other f-HLH-5 mutations have been identified. Collectively, data strongly suggest that STXBP2-R190C is a deleterious variant that may act in a dominant-negative manner by probably stabilizing non-productive interactions between STXBP2/STX11 complex and other still unknown factors such as the membrane surface or Munc13-4 protein and thus impairing the release of cytolytic granules. In addition to the contribution of STXBP2-R190C to f-HLH, the accompanied G6PD mutation may have compounded the clinical symptoms; however, the extent by which G6PD deficiency has contributed to HLH in our patient remains unclear.
| S-EPMC7580532 | biostudies-literature