Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)

Pagel, Julia; Beutel, Karin; Lehmberg, Kai; Koch, Florian; Maul-Pavicic, Andrea; Rohlfs, Anna-Katharina; Al‐Jefri, Abdullah; Beier, Rita; Ousager, Lilian Bomme; Ehlert, Karoline; Groß‐Wieltsch, Ute; Jorch, Norbert; Kremens, Bernhard; Pekrun, Arnulf; Sparber‐Sauer, Monika; Mejstříková, Ester; Wawer, Angela; Ehl, Stephan; Stadt, Udo zur; Janka, Gritta

doi:10.1182/blood-2011-12-398958

Cited by 143 publications

(131 citation statements)

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“…The proportion of patients with early-onset HLH before 12 months of age, as a parameter indicating the severity of the genetic defect, was in the same range in all groups: group I, 9/14 patients (64%); group II, 5/8 patients (63%); and groups III/IV, 11/18 (61%). FHL mutations previously reported as clearly hypomorphic 20,21 were found in the same proportion of patients in group I (2/14; 14%), group II (1/8; 13%), and groups III/IV (2/18; 11%). In the latter, however, hypomorphic mutations were only found in patients with partial flares and not with full systemic or CNS reactivations.…”

Section: Comparisons Between Patient Groupssupporting

confidence: 58%

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

Hartz

Marsh

Rao

et al. 2016

Blood

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Key Points• Donor chimerism .20%-30% usually protects against late disease reactivation after day 180 post stem cell transplantation for primary HLH.• Lower levels do not inevitably result in reactivations. The risks of intervention must be weighed against the risk of reactivation.Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000HLH ( -2013 and DC permanently or transiently <75% (overall, CD3 1 , CD56 1 ) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations ( ‡5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n 5 11, partial flare n 5 3, isolated central nervous system reactivation n 5 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3 1 if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were £10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment. (Blood. 2016;127(25):3281-3290)

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Section: Comparisons Between Patient Groupssupporting

confidence: 58%

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

Hartz

Marsh

Rao

et al. 2016

Blood

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“…Two patients were transplanted before the appearance of HLH; one patient with Griscelli syndrome type 2 and one patient with XIAP deficiency for whom HSCT was performed for intractable inflammatory bowel disease. Select aspects of 3 XIAP deficiency patients 10 and 5 FHL5 patients 11 are included in other reports. A fludarabine dose of 150 mg/m² or 5 mg/kg was administered to 16 patients from Day -7 until Day -3 (±1 day).…”

Section: Patients' Characteristics Conditioning Regimen and Gvhd Promentioning

confidence: 99%

“…However, the FHL5-related enteropathy persisted in both patients, as described previously. 11 In both patients with IBD due to XIAP-deficiency, inflammatory activity ceased after HSCT.…”

Section: Overall Outcomementioning

confidence: 99%

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

et al. 2013

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“…Biallelic hypomorphic mutations in HLH genes, which do not fully abolish cytotoxicity, are associated with late-onset of HLH in adults up to the age of 62 years. [24][25][26][27] Furthermore, adults with HLH have been found to carry a monoallelic mutation in one or more HLH-associated genes. 26,[28][29][30] This observation prompted the hypothesis whereby, additive effects of monoallelic variants in genes encoding cytotoxic effector proteins may account for some cases of HLH.…”

Section: Introductionmentioning

confidence: 99%

Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice

Sepulveda

Garrigue

Maschalidi

et al. 2016

Blood

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Key Points• The accumulation of monoallelic mutations in HLH-causing genes impairs lymphocyte cytotoxicity contributing to HLH immunopathology in mice. • A polygenic model may account for some of the cases of secondary HLH observed in humans.Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disease. Inherited forms of HLH are caused by biallelic mutations in several effectors of granule-dependent lymphocyte-mediated cytotoxicity. A small proportion of patients with a so-called "secondary" form of HLH, which develops in the aftermath of infection, autoimmunity, or cancer, carry a monoallelic mutation in one or more HLH-associated genes. Although this observation suggests that HLH may have a polygenic mode of inheritance, the latter is very difficult to prove in humans. In order to determine whether the accumulation of partial genetic defects in lymphocyte-mediated cytotoxicity can contribute to the development of HLH, we generated mice that were doubly or triply heterozygous for mutations in HLH-associated genes, those coding for perforin, Rab27a, and syntaxin-11. We found that the accumulation of monoallelic mutations did indeed increase the risk of developing HLH immunopathology after lymphocytic choriomeningitis virus infection. In mechanistic terms, the accumulation of heterozygous mutations in the two degranulation genes Rab27a and syntaxin-11, impaired the dynamics and secretion of cytotoxic granules at the immune synapse of T lymphocytes. In addition, the accumulation of heterozygous mutations within the three genes impaired natural killer lymphocyte cytotoxicity in vivo. The genetic defects can be ranked in terms of the severity of the resulting HLH manifestations. Our results form the basis of a polygenic model of the occurrence of secondary HLH. (Blood. 2016;127(17):2113-2121

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Distinct mutations in STXBP2 are associated with variable clinical presentations in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL5)

Abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined

Cited by 143 publications

References 45 publications

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice

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