Progressive neurologic disorder: Initial manifestation of hemophagocytic lymphohistiocytosis

Murphy, Claire; Nanthapisal, Sira; Gilmour, Kimberly; Laurent, S; D’Arco, Felice; Hemingway, Cheryl; Brogan, Paul A.; Eleftheriou, Despina

doi:10.1212/wnl.0000000000002729

Cited by 14 publications

(16 citation statements)

References 7 publications

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“…25,26,38 Some very severe immunological diseases, such as HLH, may initially present with a neuroinflammatory phenotype and ultimately require allogeneic HSCT if death is to be prevented. 39,40 We therefore investigated the diagnostic utility of a targeted NIP, acknowledging the genetic heterogeneity among the many differential diagnoses that must be considered. The NIP proved to be reliable in the validation stage and was associated with molecular diagnosis in a cohort of undiagnosed pediatric patients referred to our specialist service with suspected neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Although the neurological manifestations of HLH have long been recognized in the context of typical systemic and hematological features, isolated neurological disease as the initial presentation of HLH is also increasingly recognized. 39,40 The molecular diagnoses made in these cases allowed us to fast-track these patients to allogeneic HSCT and avoid unnecessary exposure to untargeted cytotoxic therapies.…”

Section: Discussionmentioning

confidence: 99%

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Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation

et al. 2019

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IMPORTANCE Neuroinflammatory disorders are a range of severe neurological disorders causing brain and spinal inflammation and are now increasingly recognized in the pediatric population. They are often characterized by marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. OBJECTIVE To develop and evaluate a next-generation sequencing panel targeting genes causing neuroinflammation or mimicking neuroinflammation. DESIGN, SETTING, AND PARTICIPANTS Cohort study in which a total of 257 genes associated with monogenic neuroinflammation and/or cerebral vasculopathy, including monogenic noninflammatory diseases mimicking these entities, were selected. A customized enrichment capture array, the neuroinflammation gene panel (NIP), was created. Targeted high-coverage sequencing was applied to DNA samples taken from eligible patients referred to Great Ormond Street Hospital in London,

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation

et al. 2019

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“…Table 1 and Figure 1 summarise the clinical, paraclinical and imaging features. Three patients have been reported elsewhere [3][4][5] . A full description of all the patients is provided in supplementary material (case vignettes).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Moreover, the patient never showed any sign of systemic HLH. Previous evidence suggest that primary HLH may also represent the underlying cause of unknown CNS inflammation even in the absence of overt clinical signs of HLH, suggesting that FHL should be included in the differential diagnosis of unclassified progressive neuroinflammatory disease ( 44 – 50 ). T and NK cell degranulation assays and the evaluation of the expression of intracellular perforin can be used for the prompt identification of such patients, allowing a targeted treatment ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Two Brothers with Atypical UNC13D-Related Hemophagocytic Lymphohistiocytosis Characterized by Massive Lung and Brain Involvement

et al. 2017

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Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition. Variants in different genes have been associated with the familial forms of the syndrome (FHL), usually presenting within the first 2 years of life. Due to increasing awareness of the signs and symptoms of HLH and a better understanding of the genetic basis of the disease, FHL has been increasingly diagnosed in patients presenting beyond infancy. Here, we report on two brothers with atypical, late-onset HLH in which whole exome sequencing revealed a homozygous pathogenic UNC13D variant. In the first brother, the clinical phenotype was dominated by a massive lung involvement. In the second brother a progressive neurological deterioration was observed. In both cases, the clinical manifestations at symptom onset were misleading, making the diagnosis difficult to achieve. This report expands the spectrum of clinical presentations of FLH3. Moreover, it highlights the importance to warn clinicians to keep a high level of suspicion in patients presenting with fever, cytopenia, splenomegaly of unknown origin, and unresponsiveness to conventional treatment even beyond early childhood. Moreover, this report emphasizes that insidious neurologic symptoms may represent the initial or sole presenting sign of FHL, even in the absence of peripheral signs of activation.

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Progressive neurologic disorder: Initial manifestation of hemophagocytic lymphohistiocytosis

Cited by 14 publications

References 7 publications

Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation

Development and Validation of a Targeted Next-Generation Sequencing Gene Panel for Children With Neuroinflammation

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

Two Brothers with Atypical UNC13D-Related Hemophagocytic Lymphohistiocytosis Characterized by Massive Lung and Brain Involvement

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