Hemophagocytic syndrome triggered by intense physical activity and viral infection in a young adult female with three heterozygous mutations in Munc-18-2

Olivera Marković; Dragana Janić; Milorad Pavlović; Ljiljana Tukić; Srdja Janković; Branka Filipović; Dragomir Marisavjević

doi:10.2298/VSP150701224M

Olivera Marković Clinical Hospital Center Bežanijska kosa, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Dragana Janić Faculty of Medicine, University of Belgrade, Belgrade, Serbia; University Children’s Hospital, Belgrade, Serbia
Milorad Pavlović Faculty of Medicine, University of Belgrade, Belgrade, Serbia; Clinic of Infectious Diseases, Belgrade, Serbia.
Ljiljana Tukić Clinic of Haematology, Military Medical Academy, Belgrade, Serbia; Faculty of Medicine of the Military Medical Academy, University of Defence, Belgrade, Serbia
Srdja Janković Clinical Hospital Center Bežanijska kosa, Belgrade, Serbia; University Children’s Hospital, Belgrade, Serbia.
Branka Filipović Clinical Hospital Center Bežanijska kosa, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Dragomir Marisavjević Clinical Hospital Center Bežanijska kosa, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.

DOI: https://doi.org/10.2298/VSP150701224M

Keywords: lymphohistiocytosis, hemophagocytic, inflammation, immunologic factors, physical exertion, ebstein-barr virus infections, mutation, diagnosis, differential, drug therapy,

Abstract

Introduction. Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially life-threatening, hyperinflammatory syn-drome caused by severe hypercytokinemia due to a highly stimulated, but ineffective immune response. Case report. We reported a 19-year-old woman presenting with fever, muscle and joint pain and sore throat. After diagnostic procedures we made the diagnosis of hemophagocytic lymphohistiocytosis (7 of 8 HLH-2004 diagnostic criteria) caused by Ebstein-Barr viral infection and trigerred by the intense physical activity. Genetic analysis showed three different sequence changes in Munc-18-2, two splice acceptor side mutations/changes affecting exon 10 (c.795–4 C > T) and exon 15 (c.1247–10 C > T) and a missense mutation c.1375 C > T; p.Arg 459 Trp. All mutations were in heterozygous state and their significance in pathogensis of HLH is not clear. After treatment with corticosteroids and cyclosporin A complete clinical remission was achieved. Conclusion. The presented case history suggests the possibility that mutations of undetermined clinical signi-ficance in a gene associated with primary HLH may underlie some cases of secondary HLH, probably by causing a partial, rather than total or subtotal, impairment of encoded protein function. Our case also suggests that strenuous physical activity (in apparent synergy with viral infection) can trigger HLH.

Author Biography

Olivera Marković, Clinical Hospital Center Bežanijska kosa, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.

Department of Hematology

References

Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: Diagnosis, pathophysiology, treatment, and future perspectives. Ann Med 2006; 38(1): 20−31.

Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: Updates and evolving concepts. Curr Opin Pediatr 2012; 24(1): 9−15.

Janka GE. Hemophagocytic syndromes. Blood Rev 2007; 21(5): 245−53.

Henter J, Horne A, Aricó M, Egeler MR, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48(2): 124−31.

zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 2005; 14(6): 827−34.

Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 2009; 85(4): 482−92.

Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007; 7(12): 814−22.

Jordan MB, Filipovich AH. Hematopoietic cell transplantation for hemophagocytic lymphohistocytosis a jorney of thousand miles begins with single (big) step. Bone Marrow Transplantation 2008; 42: 433–7.

Rohr J, Beutel K, Maul-Pavicic A, Vraetz T, Thiel J, Warnatz K, et al. Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica 2010; 95(12): 2080−7.

Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166(2): 95−109.

Pedersen BK, Bruunsgaard H, Jensen M, Toft AD, Hansen H, Ostrowski K. Exercise and the immune system: Influence of nutrition and ageing. J Sci Med Sport 1999; 2(3): 234−52.

Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL, MacLean DA, Pedersen BK. Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage. J Physiol 1997; 499 (Pt 3): 833−41.