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Germline Compound Heterozygous Variants Identified in the STXBP2 Gene Leading to a Familial Hemophagocytic Lymphohistiocytosis Type 5: A Case Report.

ABSTRACT: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, potentially fatal autosomal-recessive immunodeficiency, and STXBP2 mutations have been associated with FHL type 5 (FHL-5). Here, we report a case of a 2-year-old boy who presented with recurrent fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, and hypofibrinogenemia since 4 months of age. His genetic analysis revealed a compound heterozygosity of the STXBP2 gene with a described pathogenic mutation, c.1247-1G>C (splicing acceptor site), harbored by his father and a likely pathogenic variant of uncertain significance (VUS), c.704G>A (p.Arg235Gln), harbored by his mother. He was diagnosed as compound heterozygous for FHL-5 and was treated with the HLH-2004 protocol. Since treatment, this patient has been in remission, and he is being evaluated for a hematopoietic stem cell transplantation (HSCT).

SUBMITTER: Dantas VM

PROVIDER: S-EPMC8264126 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Familial hemophagocytic lymphohistiocytosis type 5 in a Chinese Tibetan patient caused by a novel compound heterozygous mutation in STXBP2.

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

Adult onset type 2 familial hemophagocytic lymphohistiocytosis with <i>PRF1</i> c.65delC/c.163C>T compound heterozygous mutations: A case report.

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

Molecular basis of familial hemophagocytic lymphohistiocytosis.

Project description: Not available

| S-EPMC2857182 | biostudies-literature

Familial Hemophagocytic Lymphohistiocytosis secondary to UNC13D mutation: a report of two cases.

Project description:BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by some clinical signs (e.g., non-remitting fever, hepatosplenomegaly) and laboratory findings (e.g., cytopenia, increased ferritin level, hypofibrinogenemia, lipid disorders, coagulopathy, and multiple organ failure). Depending on the etiology, HLH is divided into familial (i.e., primary) and acquired (i.e., secondary) forms. Familial HLH (FHL), an autosomal recessive condition, is classified into five subtypes based on underlying genetic defects. The PRF1, STX11, UNC13D, HPLH1, and STXBP2 are the most well-known genes of this type which are related to granule-mediated cytotoxic T and Natural killer (NK) cells. The treatment is based on the HLH-2004 protocol.Case presentationThe current report presents two cases of HLH with presentations different from each other and previously reported cases. Case 1 was a 15-month-old boy with fever, skin rash, splenomegaly, and bicytopenia, raised triglyceride levels, AST (aspartate transaminase), and ALT (alanine aminotransferase), normal ferritin, and abundant hemophagocytic cell in bone marrow aspiration. He was diagnosed with HLH and received HLH protocol as treatment. The patient had a homozygous intronic mutation; NM_199242: c.2448-13G > A in UNC13D. The associated disease was Familial Hemophagocytic Lymphohistiocytosis 3 (FHL3). Case 2, a 37-day-old female presented with fever, a history of neonatal cholestasis, and huge hepatosplenomegaly. Her whole-exome sequencing report manifested that the patient had the same mutation as case 1. Unfortunately, both patients passed away.ConclusionThe sequencing of the entire UNC13D gene (coding and non-coding regions) is an applicable and valuable diagnostic procedure for the detection of deep intronic splicing variants and large inversions in patients with atypical manifestations of HLH (such as normal ferritin or triglyceride and cholesterol).

| S-EPMC9675162 | biostudies-literature

STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.

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

Familial Hemophagocytic Lymphohistiocytosis Presenting as Hydrops Fetalis.

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

Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion.

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.

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Project description:Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and fatal autosomal recessive immune disorder characterized by uncontrolled activation of T and NK cells, macrophages, and overproduction of inflammatory cytokines. Early hematopoietic cell transplantation (HCT) is required for long-term survival. Current therapy is based on the HLH-94/2004 protocol, but is insufficient to fully control disease activity. This case report describes an infant with FHL type 3 who, despite initial therapy with dexamethasone and etoposide, showed aberrant cytokine levels, including interleukin-18 (IL-18), chemokine ligand 9 (CXCL9), soluble interleukin-2 receptor (sIL-2R), and soluble tumor necrosis factor receptor type II (sTNF-RII). The Janus kinase inhibitor ruxolitinib was therefore coadministered. The patient was treated with dose-adjusted ruxolitinib guided by cytokine profiles, and was successfully prepared for HCT. The results demonstrate the effectiveness and safety of dose-adjusted ruxolitinib as a bridging therapy for FHL, and the value of monitoring cytokine levels, especially IL-18, CXCL9, sIL-2R, and sTNF-RII, as disease-activity markers for FHL.

| S-EPMC9731208 | biostudies-literature

Identification of germline variants in adults with hemophagocytic lymphohistiocytosis.

Project description: Not available

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Familial Hemophagocytic Lymphohistiocytosis Secondary to <i>PRF1</i> Mutation.

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

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