scholarly journals Histopathologic Correlates of Familial Hemophagocytic Lymphohistiocytosis Isolated to the Central Nervous System

2018 ◽  
Vol 77 (12) ◽  
pp. 1079-1084 ◽  
Author(s):  
Isaac H Solomon ◽  
Hojun Li ◽  
Leslie A Benson ◽  
Lauren A Henderson ◽  
Barbara A Degar ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Function ◽  
Nk Cell ◽  
Systemic Disease ◽  
Cytotoxic T Cell ◽  
Compound Heterozygous ◽  
Hematopoietic Stem ◽  
Familial Hemophagocytic Lymphohistiocytosis

AbstractFamilial hemophagocytic lymphohistiocytosis (HLH) is an immune hyperactivation syndrome caused by mutations in genes associated with cytotoxic T-cell and NK-cell function. While neurological manifestations frequently accompany systemic inflammation at initial presentation, isolated central nervous system (CNS) involvement is rare, and the histological correlates are not well described. We present 3 patients (ages 5, 6, and 7 years) with CNS-isolated familial HLH, who presented with a variety of neurological symptoms and underwent brain biopsies for multifocal enhancing supratentorial and infratentorial lesions. Biopsy slides from all 3 patients revealed similar findings: perivascular lymphocytes, predominantly CD3+ T-cells (CD4>CD8) with occasional intramural infiltration of small vessels; scattered histiocytes without hemophagocytosis; parenchymal and leptomeningeal inflammation varying from mild and focal to severe and sheet-like with associated destructive lesions. There was no evidence of demyelination, neoplasia, or infection. Genetic testing identified compound heterozygous mutations in PRF1 (Patients 1 and 2) and UNC13D (Patient 3), with no evidence of systemic disease except decreased NK-cell function. All 3 patients were treated with hematopoietic stem cell transplantation with marked improvement of symptoms. These findings combined with the poor outcomes associated with delayed diagnosis and lack of aggressive treatment highlight the need to consider HLH in the differential diagnosis of inflammatory brain lesions.

Exploring the Intersection of Isolated-CNS Hemophagocytic Lymphohistiocytosis and Pediatric Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids

2021 ◽  
pp. 088307382110096
Author(s):  
Carly Debinski ◽  
Stacy Goergen ◽  
Catriona McLean ◽  
Michael E. Buckland ◽  
Beena Kumar ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Treatment Options ◽  
Immune Dysregulation ◽  
Inflammatory Condition ◽  
Hematopoietic Stem ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Whole Exome ◽  
Distinct Disease

CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an extremely rare neurologic inflammatory condition. Fewer than 10 pediatric cases have been described. Debate persists as to whether it is a distinct disease or a clinical, radiologic, and histologic phenotype evolving into another disorder. We propose that CLIPPERS may be a clinical manifestation of an underlying state of immune-dysregulation. We describe the case of the youngest known report of CLIPPERS, an 18-month-old infant from Melbourne, Australia. Reviewing the literature for all reported pediatric cases, we identified that robust investigation and whole exome sequencing was underutilized and proposed diagnostic criteria were frequently unmet. Particular focus should be paid to genes known to cause familial hemophagocytic lymphohistiocytosis (HLH), with the CLIPPERS phenotype manifesting as a form of isolated central nervous system (CNS)-HLH in some patients. Curative treatment options such as hematopoietic stem cell transplantation may be appropriate for some patients and should be considered early.

scholarly journals Jinx, an MCMV susceptibility phenotype caused by disruption of Unc13d: a mouse model of type 3 familial hemophagocytic lymphohistiocytosis

2007 ◽  
Vol 204 (4) ◽  
pp. 853-863 ◽  
Author(s):  
Karine Crozat ◽  
Kasper Hoebe ◽  
Sophie Ugolini ◽  
Nancy A. Hong ◽  
Edith Janssen ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Cell Function ◽  
Nk Cell ◽  
Lymphocytic Choriomeningitis ◽  
Chromosome 11 ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Cytokine Levels ◽  
Antigen Presenting ◽  
Type 3 ◽  
Mouse Chromosome 11

Mouse cytomegalovirus (MCMV) susceptibility often results from defects of natural killer (NK) cell function. Here we describe Jinx, an N-ethyl-N-nitrosourea–induced MCMV susceptibility mutation that permits unchecked proliferation of the virus, causing death. In Jinx homozygotes, activated NK cells and cytotoxic T lymphocytes (CTLs) fail to degranulate, although they retain the ability to produce cytokines, and cytokine levels are markedly elevated in the blood of infected mutant mice. Jinx was mapped to mouse chromosome 11 on a total of 246 meioses and confined to a 4.60–million basepair critical region encompassing 122 annotated genes. The phenotype was ascribed to the creation of a novel donor splice site in Unc13d, the mouse orthologue of human MUNC13-4, in which mutations cause type 3 familial hemophagocytic lymphohistiocytosis (FHL3), a fatal disease marked by massive hepatosplenomegaly, anemia, and thrombocytopenia. Jinx mice do not spontaneously develop clinical features of hemophagocytic lymphohistiocytosis (HLH), but do so when infected with lymphocytic choriomeningitis virus, exhibiting hyperactivation of CTLs and antigen-presenting cells, and inadequate restriction of viral proliferation. In contrast, neither Listeria monocytogenes nor MCMV induces the syndrome. In mice, the HLH phenotype is conditional, which suggests the existence of a specific infectious trigger of FHL3 in humans.

scholarly journals Frequency and Severity of Central Nervous System Lesions in Hemophagocytic Lymphohistiocytosis

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 794-800 ◽  
Author(s):  
Elie Haddad ◽  
Maria-Luisa Sulis ◽  
Nada Jabado ◽  
Stephane Blanche ◽  
Alain Fischer ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Disease Progression ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Systemic Disease ◽  
Neurological Symptoms ◽  
Treatment Modalities ◽  
Remission Induction ◽  
Cns Involvement ◽  
Cns Disease

Abstract We have retrospectively assessed the neurological manifestations in 34 patients with hemophagocytic lymphohistiocytosis (HLH) in a single center. Clinical, radiological, and cerebrospinal fluid (CSF ) cytology data were analyzed according to treatment modalities. Twenty-five patients (73%) had evidence of central nervous system (CNS) disease at time of diagnosis, stressing the frequency of CNS involvement early in the time course of HLH. Four additional patients who did not have initial CNS disease, who did not die early from HLH complications, and who were not transplanted, also developed a specific CNS disease. Therefore, all surviving and nontransplanted patients had CNS involvement. Initially, CNS manifestations consisted of isolated lymphocytic meningitis in 20 patients and meningitis with clinical and radiological neurological symptoms in nine patients. For these nine patients, neurological symptoms consisted of seizures, coma, brain stem symptoms, or ataxia. The outcome of patients treated by systemic and intrathecal chemotherapy and/or immunosuppression exclusively (n = 16) was poor, as all died following occurrence of multiple relapses or CNS disease progression in most cases. Bone marrow transplantation (BMT) from either an HLA identical sibling (n = 6) or haplo identical parent (n = 3) was performed in nine patients, once first remission of CNS and systemic disease was achieved. Seven are long-term survivors including three who received an HLA partially identical marrow. All seven are off treatment with normal neurological function and cognitive development. In four other patients, BMT performed following CNS relapses was unsuccessful. Given the frequency and the poor outcome of CNS disease in HLH, BMT appears, therefore, to be the only available treatment procedure that is capable of preventing HLH CNS disease progression and that can result in cure when performed early enough after remission induction.

scholarly journals Central nervous system–restricted familial hemophagocytic lymphohistiocytosis responds to hematopoietic cell transplantation

2019 ◽  
Vol 3 (4) ◽  
pp. 503-507 ◽  
Author(s):  
Hojun Li ◽  
Leslie A. Benson ◽  
Lauren A. Henderson ◽  
Isaac H. Solomon ◽  
Alyssa L. Kennedy ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cell Transplantation ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Key Points

Key Points Familial HLH can present as chronic isolated neuroinflammation. CNS-isolated HLH responds to hematopoietic cell transplantation.

scholarly journals Isolated central nervous system familial hemophagocytic lymphohistiocytosis (fHLH) presenting as a mimic of demyelination in children

2021 ◽  
pp. 135245852110535
Author(s):  
Amitav Parida ◽  
Omar Abdel-Mannan ◽  
Kshtiji Mankad ◽  
Katharine Foster ◽  
Sithara Ramdas ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Haematopoietic Stem Cell ◽  
High Morbidity ◽  
Cns Inflammation ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Panel Testing ◽  
Immune Therapies ◽  
Adults And Children

Isolated central nervous system (CNS) presentations of haemophagocytic lymphohistiocytosis (HLH), traditionally a systemic inflammatory condition, have been reported in adults and children. We identified nine patients with a diagnosis of isolated CNS familial hemophagocytic lymphohistiocytosis (fHLH) with symptom onset <18 years of age, and one asymptomatic sibling. Children with atypical chronic/recurrent CNS inflammation should be considered for immunological and genetic panel testing for fHLH even in the absence of any systemic inflammatory features. Despite haematopoietic stem cell transplantation (HSCT) being a mainstay of treatment, treatment failure and high morbidity and mortality post-HSCT suggest that alternative immune therapies may be worth considering.

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

2021 ◽  
Vol 9 ◽  
Author(s):  
Vera Maria Dantas ◽  
Cassandra Teixeira Valle ◽  
Roberta Piccin de Oliveira ◽  
Mylena Taíse Azevedo L. Bezerra ◽  
Cleia Teixeira do Amaral ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Pathogenic Mutation ◽  
Recurrent Fever ◽  
Compound Heterozygous ◽  
Acceptor Site ◽  
Hematopoietic Stem ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Compound Heterozygous Variants

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&gt;C (splicing acceptor site), harbored by his father and a likely pathogenic variant of uncertain significance (VUS), c.704G&gt;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).

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