FATAL SIBLING CASES OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (FHL) WITH MUNC13–4 MUTATIONS: Case Reports

@article{Nakao2008FATALSC,
  title={FATAL SIBLING CASES OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (FHL) WITH MUNC13–4 MUTATIONS: Case Reports},
  author={Tomohei Nakao and Takashi Shimizu and Takashi Fukushima and Makoto Saito and Miho Okamoto and Masatoshi Sugiura and Ken Yamamoto and Ikuyo Ueda and Shinsaku Imashuku and Chie Kobayashi and Kazutoshi Koike and Masahiro Tsuchida and Ryo Sumazaki and Akira Matsui},
  journal={Pediatric Hematology and Oncology},
  year={2008},
  volume={25},
  pages={171 - 180}
}
The authors report here sibling cases of familial hemophagocytic lymphohistiocytosis (FHL) type 3 that took fatal courses despite intensive treatment. The older brother achieved remission by immunochemotherapy, but a central nervous system lesion occurred before the introduction of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patient died on day +1 of allo-HSCT due to progression of the disease. The younger brother developed symptoms of hemophagocytic lymphohistiocytosis… 
A case of fetal‐onset type 3 familial hemophagocytic lymphohistiocytosis surviving without severe complications after early diagnosis and treatment
TLDR
The rapid progress of hepatomegaly, liver dysfunction, and generalized edema suggested hemophagocytic lymphohistiocytosis (HLH), and five of the eight criteria for HLH diagnosis were met on day of life 2 (DOL 2).
Hydrops fetalis and early neonatal multiple organ failure in familial hemophagocytic lymphohistiocytosis.
TLDR
The first case of hydrops fetalis caused by FHLH is presented, confirmed by DNA analysis and should be included in the differential diagnosis of non-immune hydrops Fetalis and neonatal multiple organ failure.
Diagnostic challenges in a child with familial hemophagocytic lymphohistiocytosis type 3 (FHLH3) presenting with fulminant neurological disease
TLDR
Diagnostic criteria for hemophagocytic lymphohistiocytosis were not consistently met, despite aggressive disease, and expeditious molecular testing and genetic counseling for FHLH mutations in cases of undiagnosed inflammatory CNS disease in the pediatric population are strongly recommended.
Characteristics of hemophagocytic lymphohistiocytosis in neonates: a nationwide survey in Japan.
TLDR
HLH is rare in neonates and has a poor prognosis, and early diagnosis and immediate treatment are required when considering the possibility of herpes simplex virus-associated or familial HLH.
Hemophagocytic lymphohistiocytosis mimicking neonatal hemochromatosis
Abstract Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal illness characterized by impaired natural killer (NK) cell and cytotoxic T-cell function. Patients develop systemic
French Retrospective Multicentric Study of Neonatal Hemochromatosis: Importance of Autopsy and Autoimmune Maternal Manifestations
TLDR
This work highlights the importance of autopsy in cases of neonatal haemochromatosis and marshals additional data in support of the hypothesis that neonatal hemochROMatosis could reflect maternal immune system dysregulation.
Congenital Hemophagocytic Lymphohistiocytosis in a Preterm Infant: Cytokine Profile and a Review of the Disease
TLDR
A preterm infant with very low birth weight was born with fetal onset familial hemophagocytic lymphohistiocytosis, and selectively elevated expression of interleukin-6 and chemokines in the cord blood of the patient.
First characterization of platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 3 (FHL-3).
TLDR
FHL, a rare autosomal recessive disorder of lymphocyte cytotoxicity, is caused by mutations in genes encoding perforin (FHL-2) or proteins important for intracellular trafficking/exocytosis of per forin-containing lytic granules: Munc13-4.
Hyperferritinemia in hemophagocytic lymphohistiocytosis and related diseases
TLDR
As clearly discussed in the previous articles, HLH is the first diagnosis to be suspected for any patients showing hyperferritinemia, however, careful and laborious diagnostic measures are needed to clarify the unknown causes of hyperferritic disease, which may be related or unrelated with HLH episodes, keeping in mind of various metabolic disorders.
Depressed Levels of Interferon-Gamma and HLA-DR+CD3+ T Cells in Infants with Transient Hyperferritinemia
TLDR
Compared the levels of HLA-DR+CD3+ T-cell subsets and interferon-gamma (IFN-γ) in the peripheral blood between infants and FHL cases, measurement of activated T cells and serum IFN-α might help differentiate FHL in febrile infants with transient hyperferritinemia.
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References

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TLDR
FHL may have a broad clinical spectrum, and further analysis on its phenotype-genotype association is required to establish an appropriate treatment strategy, including immunochemotherapy and stem cell transplantation in the future.
Novel Munc13–4 mutations in children and young adult patients with haemophagocytic lymphohistiocytosis
TLDR
Because these patients may develop the disease during adolescence or even later, haematologists should include FHL2 and FHL3 in the differential diagnosis of young adults with fever, cytopenia, splenomegaly and hypercytokinaemia.
Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors.
TLDR
It is concluded that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell-depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetic identical donor.
Treatment of Familial Hemophagocytic Lymphohistiocytosis With Bone Marrow Transplantation From HLA Genetically Nonidentical Donors
TLDR
It is concluded that an immunologic approach in terms of drugs used to obtain disease remission and a conditioning regimen that includes antiadhesion molecules in T-cell-depleted BMT from HLA genetically nonidentical donors is an alternative treatment that warrants further study in FHL patients who lack a suitable HLA genetic identical donor.
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TLDR
A 3-day-old neonate with confirmed HLH who had a stormy course and a fatal outcome to the disease process, in spite of early chemotherapy is reported here, believed to be the youngest reported case of HLH from Middle East.
Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions.
TLDR
The results suggest an association between the type of genetic mutation in FHL cases and the magnitude of CTL cytolytic activity and age at onset.
Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation.
TLDR
HLH-94 is very effective, allowing BMT in most patients, and survival of children with HLH has been greatly improved.
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TLDR
It is now considered that FHL is a disorder of T-cell function; moreover, clonal proliferation of T lymphocytes is observed in a few FHL patients, and cytotoxicity of these T lymphocyte for target cells is usually impaired.
Bone marrow transplantation in a child with hemophagocytic lymphohistiocytosis using a less toxic conditioning regimen.
TLDR
The results in this patient suggest that a less toxic regimen is feasible and permits rapid engraftment without compromising the effectiveness of chemotherapy and the conditioning regimen was adequate for the eradication of the disease.
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TLDR
The high mortality of HLH supports a role for allogeneic BMT in selected cases, particularly those with a familial basis or under 2 years at presentation, as well as those with proven or suspected virus‐associated HLH.
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