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Perforin Deficiency

MedGen UID:
925941
•Concept ID:
C4288409
•
Disease or Syndrome

Definition

A condition of decreased or absent presence of perforin. Deficiency of this protein is associated with T-cell lymphoblastic lymphoma, aplastic anemia, hemophagocytic lymphohistiocytosis familial type 2, autoimmune lymphoproliferative syndrome and other lymphoproliferative disorders, including various forms of lymphoma. [from NCI]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPerforin Deficiency

Professional guidelines

PubMed

Low Percentage of Perforin-Expressing NK Cells during Severe SARS-CoV-2 Infection: Consumption Rather than Primary Deficiency.
Kundura L, Cezar R, Ballongue E, André S, Michel M, Mettling C, Lozano C, Vincent T, Muller L, Lefrant JY, Roger C, Claret PG, Duvnjak S, Loubet P, Sotto A, Tran TA, Estaquier J, Corbeau P
J Immunol 2024 Apr 1;212(7):1105-1112. doi: 10.4049/jimmunol.2300359. PMID: 38345346

Recent clinical studies

Etiology

High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy.
Hadžić N, Molnar E, Height S, Kovács G, Dhawan A, Andrikovics H, Worth A, Gilmour KC
J Pediatr 2022 Nov;250:67-74.e1. Epub 2022 Jul 11 doi: 10.1016/j.jpeds.2022.07.006. PMID: 35835228
Toxicity Induced by a Bispecific T Cell-Redirecting Protein Is Mediated by Both T Cells and Myeloid Cells in Immunocompetent Mice.
Godbersen-Palmer C, Coupet TA, Grada Z, Zhang SC, Sentman CL
J Immunol 2020 Jun 1;204(11):2973-2983. Epub 2020 Apr 15 doi: 10.4049/jimmunol.1901401. PMID: 32295875Free PMC Article
To Transplant or Not to Transplant? Late-Onset Primary HLH in a Patient: A Case Report and Review of Literature.
Ashok V, Kent P, Tamulonis K, Vavra K
J Pediatr Hematol Oncol 2019 Aug;41(6):482-488. doi: 10.1097/MPH.0000000000001531. PMID: 31219909
Spectrum of Atypical Clinical Presentations in Patients with Biallelic PRF1 Missense Mutations.
Tesi B, Chiang SC, El-Ghoneimy D, Hussein AA, Langenskiöld C, Wali R, Fadoo Z, Silva JP, Lecumberri R, Unal S, Nordenskjöld M, Bryceson YT, Henter JI, Meeths M
Pediatr Blood Cancer 2015 Dec;62(12):2094-100. Epub 2015 Jul 16 doi: 10.1002/pbc.25646. PMID: 26184781
Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis.
Feldmann J, Le Deist F, Ouachée-Chardin M, Certain S, Alexander S, Quartier P, Haddad E, Wulffraat N, Casanova JL, Blanche S, Fischer A, de Saint Basile G
Br J Haematol 2002 Jun;117(4):965-72. doi: 10.1046/j.1365-2141.2002.03534.x. PMID: 12060139

Diagnosis

High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy.
Hadžić N, Molnar E, Height S, Kovács G, Dhawan A, Andrikovics H, Worth A, Gilmour KC
J Pediatr 2022 Nov;250:67-74.e1. Epub 2022 Jul 11 doi: 10.1016/j.jpeds.2022.07.006. PMID: 35835228
Systemic and Nodular Hyperinflammation in a Patient with Refractory Familial Hemophagocytic Lymphohistiocytosis 2.
Segal JE, Daley JD, Barnum JL, Salgado CM, Reyes-Mugica M, Schneider C, Gumus S, Thakrar D, Allen SW, Canna SW
J Clin Immunol 2021 Jul;41(5):987-991. Epub 2021 Feb 11 doi: 10.1007/s10875-021-00986-9. PMID: 33570715Free PMC Article
Downregulation of CD5 and dysregulated CD8(+) T-cell activation.
Wada T
Pediatr Int 2018 Sep;60(9):776-780. Epub 2018 Aug 8 doi: 10.1111/ped.13636. PMID: 29920868
Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders.
Filipovich AH
Immunol Allergy Clin North Am 2008 May;28(2):293-313, viii. doi: 10.1016/j.iac.2008.01.010. PMID: 18424334
Biology and treatment of familial hemophagocytic lymphohistiocytosis: importance of perforin in lymphocyte-mediated cytotoxicity and triggering of apoptosis.
Henter JI
Med Pediatr Oncol 2002 May;38(5):305-9. doi: 10.1002/mpo.1340. PMID: 11979453

Therapy

JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation.
Meyer LK, Verbist KC, Albeituni S, Scull BP, Bassett RC, Stroh AN, Tillman H, Allen CE, Hermiston ML, Nichols KE
Blood 2020 Aug 6;136(6):657-668. doi: 10.1182/blood.2020006075. PMID: 32530039Free PMC Article
Predominant Neurologic Manifestations Seen in a Patient With a Biallelic Perforin1 Mutation (PRF1; p.R225W).
Madkaikar M, Gupta M, Dixit A, Patil V
J Pediatr Hematol Oncol 2017 Mar;39(2):143-146. doi: 10.1097/MPH.0000000000000597. PMID: 27271812
Gene therapy for haemophagocytic lymphohistiocytosis.
Booth C, Carmo M, Gaspar HB
Curr Gene Ther 2014;14(6):437-46. doi: 10.2174/1566523214666140918112113. PMID: 25245087
VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression.
Doloff JC, Waxman DJ
Cancer Res 2012 Mar 1;72(5):1103-15. Epub 2012 Jan 11 doi: 10.1158/0008-5472.CAN-11-3380. PMID: 22237627Free PMC Article
Interleukin 21 enhances antibody-mediated tumor rejection.
Smyth MJ, Teng MW, Sharkey J, Westwood JA, Haynes NM, Yagita H, Takeda K, Sivakumar PV, Kershaw MH
Cancer Res 2008 Apr 15;68(8):3019-25. doi: 10.1158/0008-5472.CAN-07-6019. PMID: 18413772

Prognosis

Systemic and Nodular Hyperinflammation in a Patient with Refractory Familial Hemophagocytic Lymphohistiocytosis 2.
Segal JE, Daley JD, Barnum JL, Salgado CM, Reyes-Mugica M, Schneider C, Gumus S, Thakrar D, Allen SW, Canna SW
J Clin Immunol 2021 Jul;41(5):987-991. Epub 2021 Feb 11 doi: 10.1007/s10875-021-00986-9. PMID: 33570715Free PMC Article
To Transplant or Not to Transplant? Late-Onset Primary HLH in a Patient: A Case Report and Review of Literature.
Ashok V, Kent P, Tamulonis K, Vavra K
J Pediatr Hematol Oncol 2019 Aug;41(6):482-488. doi: 10.1097/MPH.0000000000001531. PMID: 31219909
Human perforin gene variation is geographically distributed.
Willenbring RC, Ikeda Y, Pease LR, Johnson AJ
Mol Genet Genomic Med 2018 Jan;6(1):44-55. Epub 2017 Dec 7 doi: 10.1002/mgg3.344. PMID: 29216683Free PMC Article
Predominant Neurologic Manifestations Seen in a Patient With a Biallelic Perforin1 Mutation (PRF1; p.R225W).
Madkaikar M, Gupta M, Dixit A, Patil V
J Pediatr Hematol Oncol 2017 Mar;39(2):143-146. doi: 10.1097/MPH.0000000000000597. PMID: 27271812
Successful treatment with liposteroid followed by reduced intensity stem cell transplantation in an infant with perforin deficiency presenting with hemophagocytic lymphohistiocytosis.
Kobayashi Y, Salih HM, Kajiume T, Nakamura K, Miyagawa S, Sato T, Nishimura S, Kobayashi M
J Pediatr Hematol Oncol 2007 Mar;29(3):178-82. doi: 10.1097/MPH.0b013e3180335030. PMID: 17356398

Clinical prediction guides

Low Percentage of Perforin-Expressing NK Cells during Severe SARS-CoV-2 Infection: Consumption Rather than Primary Deficiency.
Kundura L, Cezar R, Ballongue E, André S, Michel M, Mettling C, Lozano C, Vincent T, Muller L, Lefrant JY, Roger C, Claret PG, Duvnjak S, Loubet P, Sotto A, Tran TA, Estaquier J, Corbeau P
J Immunol 2024 Apr 1;212(7):1105-1112. doi: 10.4049/jimmunol.2300359. PMID: 38345346
High Prevalence of Hemophagocytic Lymphohistiocytosis in Acute Liver Failure of Infancy.
Hadžić N, Molnar E, Height S, Kovács G, Dhawan A, Andrikovics H, Worth A, Gilmour KC
J Pediatr 2022 Nov;250:67-74.e1. Epub 2022 Jul 11 doi: 10.1016/j.jpeds.2022.07.006. PMID: 35835228
Perforin-deficient CAR T cells recapitulate late-onset inflammatory toxicities observed in patients.
Ishii K, Pouzolles M, Chien CD, Erwin-Cohen RA, Kohler ME, Qin H, Lei H, Kuhn S, Ombrello AK, Dulau-Florea A, Eckhaus MA, Shalabi H, Yates B, Lichtenstein DA, Zimmermann VS, Kondo T, Shern JF, Young HA, Taylor N, Shah NN, Fry TJ
J Clin Invest 2020 Oct 1;130(10):5425-5443. doi: 10.1172/JCI130059. PMID: 32925169Free PMC Article
Human perforin gene variation is geographically distributed.
Willenbring RC, Ikeda Y, Pease LR, Johnson AJ
Mol Genet Genomic Med 2018 Jan;6(1):44-55. Epub 2017 Dec 7 doi: 10.1002/mgg3.344. PMID: 29216683Free PMC Article
Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm.
Chamberlain CM, Ang LS, Boivin WA, Cooper DM, Williams SJ, Zhao H, Hendel A, Folkesson M, Swedenborg J, Allard MF, McManus BM, Granville DJ
Am J Pathol 2010 Feb;176(2):1038-49. Epub 2009 Dec 24 doi: 10.2353/ajpath.2010.090700. PMID: 20035050Free PMC Article

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