Autopsy and Case Reports https://app.periodikos.com.br/journal/autopsy/article/doi/10.4322/acr.2019.101
Article / Autopsy Case Report
Fatal familial hemophagocytic lymphohistiocytosis with perforin gene (PRF1) mutation and EBV-associated T-cell lymphoproliferative disorder of the thyroid
Familial hemophagocytic lymphohistiocytosis (FHL) is a rare fatal autosomal recessive disorder of immune dysregulation. The disease presents most commonly in the first year of life; however, symptomatic presentation throughout childhood and adulthood has also been identified. Biallelic mutation in the perforin gene is present in 20%–50% of all cases of FHL. Secondary hemophagocytic lymphohistiocytosis (HLH) in association with hematological malignancies is known; however, whether mutations in HLH-associated genes can be associated with FHL and hematolymphoid neoplasms is not well documented. Also, Epstein–Barr-virus- (EBV) positive systemic T-cell lymphoproliferative disease (SE-LPD) in the setting of FHL is not clearly understood. Here, we present the case of a young boy who presented with typical features of childhood FHL harboring the perforin gene (PRF1) mutation, and had SE-LPD diagnosed on autopsy, along with evidence of recent EBV infection. The patient expired due to progressive disease. Five siblings died in the second or third decade of life with undiagnosed disease. Genetic counseling was provided to the two surviving siblings and parents, but they could not afford genetic testing. One surviving sibling has intermittent fever and is on close follow-up for possible bone marrow transplantation.
ClementiR, EmmiL, MaccarioR, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002;100(6):2266-7. [https://doi.org/10.1182/blood-2002-04-1030]. [PMID:12229880]
ZhangK, FilipovichAH, JohnsonJ, et al.Hemophagocytic Lymphohistiocytosis, Familial – Gene Review. Seattle: University of Washington; 1993-2019.
TakahashiN, MiuraI, ChubachiA, MiuraAB, NakamuraS. A clinicopathological study of 20 patients with T/natural killer (NK)-cell lymphoma-associated hemophagocytic syndrome with special reference to nasal and nasal-type NK/T-cell lymphoma. Int J Hematol. 2001;74(3):303-8. [https://doi.org/10.1007/BF02982065]. [PMID:11721967]
MacheCJ, SlavcI, SchmidC, et al. Familial hemophagocytic lymphohistiocytosis associated with disseminated T-cell lymphoma- a report of two siblings. Ann Hematol. 1994;69(2):85-91. [https://doi.org/10.1007/BF01698488]. [PMID:8080885]
de Saint BasileG, MénaschéG, FischerA. Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol. 2010;10(8):568-79. [https://doi.org/10.1038/nri2803]. [PMID:20634814]
ClementiR, DagnaL, DianzaniU, et al. Inherited perforin and Fas mutations in a patient with autoimmune lymphoproliferative syndrome and lymphoma. N Engl J Med. 2004;351(14):1419-24. [https://doi.org/10.1056/NEJMoa041432]. [PMID:15459303]
HenterJI, HorneA, AricóM, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31. [https://doi.org/10.1002/pbc.21039]. [PMID:16937360]
MhatreS, MadkaikarM, DesaiM, GhoshK. Spectrum of perforin gene mutations in Familial hemophagocytic lymphohistiocytosis (FHL) patients in India. Blood Cells Mol Dis. 2015;54(3):250-7. [https://doi.org/10.1016/j.bcmd.2014.11.023]. [PMID:25577959]
UedaI, KurokawaY, KoikeK, et al. Late-onset cases of familial hemophagocytic lymphohistiocytosis with missense perforin gene mutations. Am J Pathol. 2007;82(6):427-32. [PMID:17266056]
SmithMC, CohenDN, GreigB, et al. The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T-cell lymphoproliferative disorder. Int J Clin Exp Pathol. 2014;7(9):5738-49. [PMID:25337215]
ChiaJ, YeoKP, WhisstockJC, DunstoneMA, TrapaniJA, VoskoboinikI. Temperature sensitivity of human perforin mutants unmasks subtotal loss of cytotoxicity, delayed FHL, and a predisposition to cancer. Proc Natl Acad Sci USA. 2009;106(24):9809-14. [https://doi.org/10.1073/pnas.0903815106]. [PMID:19487666]
MadkaikarM, ShabrishS, DesaiM. Current updates on classification, diagnosis and treatment of hemophagocytic lymphohistiocytosis. Indian J Pediatr. 2016;83(5):434-43. [https://doi.org/10.1007/s12098-016-2037-y]. [PMID:26872683]
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