Diagnostic challenges in a child with familial hemophagocytic lymphohistiocytosis type 3 (FHLH3) presenting with fulminant neurological disease

Weisfeld-Adams, James D.; Frank, Yitzchak; Havalad, Vinod; Hojsak, Joanne; Posada, Roberto; Kaicker, Shipra; Wistinghausen, Birte

doi:10.1007/s00381-008-0744-z

Cited by 22 publications

(9 citation statements)

References 26 publications

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“…By examining genotype–phenotype relationships of FHL-causing mutations, it is now clear that some patients do not meet the criteria for FHL at disease onset and often present with atypical immune dysregulation, or HLH much later than was previously considered likely ( 4 , 12 , 13 ). Localized or organ-specific inflammation, particularly affecting the CNS, is increasingly being reported as an initial presentation of FHL ( 3 , 14 – 16 ), as are vasculitis ( 15 , 17 , 18 ), granulomatous pneumonitis ( 19 , 20 ), and arthritis ( 17 , 21 ). The index case discussed here had previously unreported presentations of FHL-causing gene deficiency, namely: severe growth arrest and delayed puberty, beginning at the age of 11, followed by raised ICP secondary to presumed inflammatory arachnoiditis 2 years later.…”

Section: Discussionmentioning

confidence: 99%

Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D

et al. 2017

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Bi-allelic null mutations affecting UNC13D, STXBP2, or STX11 result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL) in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of this disease, or with HLH later in life. Here, we studied two sisters with lymphocyte degranulation defects secondary to compound heterozygote missense variants in UNC13D. The older sibling presented aged 11 with linear growth arrest and delayed puberty, 2 years prior to developing transient ischemic attacks secondary to neuroinflammation and hypogammaglobulinemia, but no FHL symptoms. Her geno-identical younger sister was initially asymptomatic but then presented at the same age with severe EBV-driven infectious mononucleosis, which was treated aggressively and did not progress to HLH. The sisters had similar natural killer cell degranulation; however, while cytotoxic activity was moderately reduced in the asymptomatic patient, it was completely absent in both siblings during active disease. Following allogeneic bone marrow transplantation at the age of 15, the older child has completely recovered NK cell cytotoxicity, is asymptomatic, and has experienced an exceptional compensatory growth spurt. Her younger sister was also successfully transplanted and is currently disease free. The current study reveals previously unappreciated manifestations of FHL in patients who inherited hypomorphic gene variants and also raises the important question of whether a threshold of minimum NK function can be defined that should protect a patient from serious disease manifestations such as HLH.

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Section: Discussionmentioning

confidence: 99%

Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D

et al. 2017

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“…CSF examination usually shows elevated protein, increased number of mononuclear cells, and occasionally hemophagocytosis ( 9 , 40 , 41 ). Typical radiologic findings include demyelination or impaired myelination, gray and white matter multifocal inflammation mimicking neuroinflammatory disorders including multiple sclerosis and acute disseminated encephalomyelitis ( 41 , 42 ). FHL3 patients seem to be even more prone to develop CNS involvement.…”

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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“… 2 CNS involvement in HLH can radiologically mimic neuroinflammatory disorders including multiple sclerosis and acute disseminated encephalomyelitis. 6 Since diagnostic delay may result in fatalities or irreversible neurologic sequelae, 2 clinicians should be aware that unclassified neuroinflammatory diseases could evolve into full-blown HLH.…”

Section: Discussionmentioning

confidence: 99%

Progressive neurologic disorder: Initial manifestation of hemophagocytic lymphohistiocytosis

et al. 2016

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Diagnostic challenges in a child with familial hemophagocytic lymphohistiocytosis type 3 (FHLH3) presenting with fulminant neurological disease

Cited by 22 publications

References 26 publications

Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D

Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D

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

Progressive neurologic disorder: Initial manifestation of hemophagocytic lymphohistiocytosis

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