Monogenic Disorder Associated with Autoimmune Lymphoproliferative Syndrome-Like Phenotype: A Systematic Review
Abstract
Background: Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenia. Some of autoreactive T cells cannot become apoptosis in activation-induced cell death (AICD) pathway; therefore, they have accumulation of autoreactive TCRαβ+CD4−CD8− doublenegative T (αβ- DNT) cells, leading to cytopenia, splenomegaly, lymphadenopathy, autoimmune disorders and a greatly increased lifetime risk of lymphoma. FAS, FASL, CASP8 and CASP10 gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in ALPS-like phenotype.
Methods: A systematic literature search was performed in Web of Science, PubMed and Scopus from the earliest available date to march 2021 with standard keywords to find patients with ALPS-like phenotypes. Demographic, clinical, immunological and molecular data were extracted.
Results: In this systematic review we reported 61 patients with genetically determined ALPS-like. Most of ALPS-like cases carry mutations in the STAT3 (n=15), LRBA (n=11) and CARD11 (n=8) genes. The most common presentation was splenomegaly and lymphadenopathy followed by hepatomegaly. The most common autoimmunity was autoimmune hemolytic anemia and immune thrombocytopenic purpura followed by autoimmune neutropenia. Elevated serum immunoglobulin was reported especially in IgG, IgM and IgA.
Conclusion: In the present study, 61 patients with genetically determined ALPS-like were examined. Our results showed that most of ALPS-like cases carry mutations in the STAT3. We reported that the most common presentations were splenomegaly and lymphadenopathy. Elevated serum immunoglobulin, IL-10, vitamin B12 and increased proportion of DNT cells were reported.
1. Oliveira JB, Bidère N, Niemela JE, Zheng L, Sakai K, Nix CP, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proc Natl Acad Sci U S A. 2007; 22;104(21):8953-8.
2. Niemela JE, Lu L, Fleisher TA, Davis J, Caminha I, Natter M, et al. Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood. 2011;10;117(10):2883-6.
3. Shiota M, Yang X, Kubokawa M, Morishima T, Tanaka K, Mikami M, et al. Somatic mosaicism for a NRAS mutation associates with disparate clinical features in RAS-associated leukoproliferative disease: a report of two cases. J Clin Immunol. 2015;35(5):454-8.
4. Nabhani S, Schipp C, Miskin H, Levin C, Postovsky S, Dujovny T, et al. STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds. Clin Immunol. 2017 Aug;181:32-42.Clin Immunol. 2017;181:32-42.
5. Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K, et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood. 2011;117(10):2887-90.
6. Revel-Vilk S, Fischer U, Keller B, Nabhani S, Gámez-Díaz L, Rensing-Ehl A, et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin Immunol. 2015;159(1):84-92.
7. Takagi M, Ogata S, Ueno H, Yoshida K, Yeh T, Hoshino A, et al. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2017;139(6):1914-1922.
8. Hafezi N, Zaki‐Dizaji M, Nirouei M, Asadi G, Sharifinejad N, Jamee M, et al. Clinical, Immunological, and Genetic Features in 780 Patients with Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS‐like diseases: A Systematic Review. Pediatr Allergy Immunol. 2021.
9. Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35-40.
10. Miano M, Cappelli E, Pezzulla A, Venè R, Grossi A, Terranova P, et al. FAS‐mediated apoptosis impairment in patients with ALPS/ALPS‐like phenotype carrying variants on CASP10 gene. Br J Haematol. 2019;187(4):502-508.
11. Takeda A, Zhang Y, Dornan G. Novel PIK3CD mutations affecting N-terminal residues of p1100d cause activated PI3Kd syndrome (APDS) in humans [published online ahead of print 13 April 2017]. J Allergy Clin Immunol. 2017;140(4):1152-1156.e10.
12. Gu H, Ma J, Chen Z, Wang J, Zhang R, Wu R. Synergistic defects of novo FAS and homozygous UNC13D leading to autoimmune lymphoproliferative syndrome-like disease: A 10-year-old Chinese boy case report. Gene. 2018;672:45-49.
13. Kucuk ZY, Charbonnier L-M, McMasters RL, Chatila T, Bleesing JJ. CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder. J Allergy Clin Immunol. 2017;140(3):862-864.e4.
14. Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M. Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis. Pediatr Blood Cancer. 2018;65(4).
15. Fernández KS, Antony R, Kumar A. Patients with" ALPS-like phenotype" diagnosed with immune dysregulation due to LRBA deficiency. Pediatr Blood Cancer. 2019;66(3):e27558.
16. Barzaghi F, Minniti F, Mauro M, Bortoli MD, Balter R, Bonetti E, et al. ALPS-like phenotype caused by ADA2 deficiency rescued by allogeneic hematopoietic stem cell transplantation. Front Immunol. 2019;9:2767.
17. Cagdas D, Halaçlı SO, Tan Ç, Lo B, Çetinkaya PG, Esenboğa S, et al. A spectrum of clinical findings from ALPS to CVID: several novel LRBA defects. J Clin Immunol. 2019;39(7):726-738.
18. Schipp C, Schlütermann D, Hönscheid A, Nabhani S, Höll J, Oommen PT, et al. EBV negative lymphoma and autoimmune lymphoproliferative syndrome like phenotype extend the clinical spectrum of primary immunodeficiency caused by STK4 deficiency. Front Immunol. 2018;9:2400.
19. Mao H, Yang W, Latour S, Yang J, Winter S, Zheng J, et al. RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. J Allergy Clin Immunol. 2018;142(2):595-604.e16.
20. Takagi M, Hoshino A, Yoshida K, Ueno H, Imai K, Piao J, et al. Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation. Pediatr Blood Cancer. 2018;65(2).
21. Westermann-Clark E, Grossi A, Fioredda F, Giardino S, Cappelli E, Terranova P, et al. RAG deficiency with ALPS features successfully treated with TCRαβ/CD19 cell depleted haploidentical stem cell transplant. Clin Immunol. 2018;187:102-103.
22. Cohen JM, Sebire NJ, Harvey J, Gaspar HB, Cathy C, Jones A, et al. Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation. Blood. 2007;110(6):2209-14.
23. Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, et al. Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117-25.
24. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591-9.
25. Sharifinejad N, Azizi G, Behniafard N, Zaki-Dizaji M, Jamee M, Yazdani R, et al. Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature. Immunol Invest. 2020;13:1-12.
26. Snow AL, Xiao W, Stinson JR, Lu W, Chaigne-Delalande B, Zheng L, et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutationsGermline CARD11 mutations in humans. J Exp Med. 2012;209(12):2247-61.
27. Gupta M, Aluri J, Desai M, Lokeshwar M, Taur P, Lenardo M, et al. Clinical, immunological, and molecular findings in four cases of B cell expansion with NF-κB and T cell anergy disease for the first time from India. Front Immunol. 2018;9:1049.
28. Outinen T, Syrjanen J, Rounioja S, Saarela J, Kaustio M, Helminen M. Constant B cell lymphocytosis since early age in a patient with CARD11 mutation: a 20-year follow-up. Clin Immunol. 2016;165:19-20.
29. Comrie WA, Faruqi AJ, Price S, Zhang Y, Rao VK, Su HC, et al. RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol. 2018;141(4):1507-1510.e8.
30. Saettini F, Pelagatti M, Sala D, Moratto D, Giliani S, Badolato R, et al. Early diagnosis of PI3Kδ syndrome in a 2 years old girl with recurrent otitis and enlarged spleen. Immunol Lett. 2017;190:279-281.
31. Matson DR, Yang DT. Autoimmune Lymphoproliferative Syndrome: An Overview. Arch Pathol Lab Med. 2020;144(2):245-251.
32. Leal-Seabra F, Costa GS, Coelho HP, Oliveira A. Unexplained lymphadenopathies: autoimmune lymphoproliferative syndrome in an adult patient. BMJ Case Rep. 2016;2016:bcr2016216758.
33. Bride K, Teachey D. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Res. 2017;6:1928.
34. Shah S, Wu E, Rao VK, Tarrant TK. Autoimmune Lymphoproliferative Syndrome: an Update and Review of the Literature. Curr Allergy Asthma Rep. 2014;14(9):462.
35. Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L, et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118(18):4798-807.
36. Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB, et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood. 2010;115(25):5164-9.
37. Teachey DT, Seif AE, Grupp SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol. 2010;148(2):205-16.
2. Niemela JE, Lu L, Fleisher TA, Davis J, Caminha I, Natter M, et al. Somatic KRAS mutations associated with a human nonmalignant syndrome of autoimmunity and abnormal leukocyte homeostasis. Blood. 2011;10;117(10):2883-6.
3. Shiota M, Yang X, Kubokawa M, Morishima T, Tanaka K, Mikami M, et al. Somatic mosaicism for a NRAS mutation associates with disparate clinical features in RAS-associated leukoproliferative disease: a report of two cases. J Clin Immunol. 2015;35(5):454-8.
4. Nabhani S, Schipp C, Miskin H, Levin C, Postovsky S, Dujovny T, et al. STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds. Clin Immunol. 2017 Aug;181:32-42.Clin Immunol. 2017;181:32-42.
5. Takagi M, Shinoda K, Piao J, Mitsuiki N, Takagi M, Matsuda K, et al. Autoimmune lymphoproliferative syndrome-like disease with somatic KRAS mutation. Blood. 2011;117(10):2887-90.
6. Revel-Vilk S, Fischer U, Keller B, Nabhani S, Gámez-Díaz L, Rensing-Ehl A, et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin Immunol. 2015;159(1):84-92.
7. Takagi M, Ogata S, Ueno H, Yoshida K, Yeh T, Hoshino A, et al. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2017;139(6):1914-1922.
8. Hafezi N, Zaki‐Dizaji M, Nirouei M, Asadi G, Sharifinejad N, Jamee M, et al. Clinical, Immunological, and Genetic Features in 780 Patients with Autoimmune Lymphoproliferative Syndrome (ALPS) and ALPS‐like diseases: A Systematic Review. Pediatr Allergy Immunol. 2021.
9. Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ, et al. Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. Blood. 2010;116(14):e35-40.
10. Miano M, Cappelli E, Pezzulla A, Venè R, Grossi A, Terranova P, et al. FAS‐mediated apoptosis impairment in patients with ALPS/ALPS‐like phenotype carrying variants on CASP10 gene. Br J Haematol. 2019;187(4):502-508.
11. Takeda A, Zhang Y, Dornan G. Novel PIK3CD mutations affecting N-terminal residues of p1100d cause activated PI3Kd syndrome (APDS) in humans [published online ahead of print 13 April 2017]. J Allergy Clin Immunol. 2017;140(4):1152-1156.e10.
12. Gu H, Ma J, Chen Z, Wang J, Zhang R, Wu R. Synergistic defects of novo FAS and homozygous UNC13D leading to autoimmune lymphoproliferative syndrome-like disease: A 10-year-old Chinese boy case report. Gene. 2018;672:45-49.
13. Kucuk ZY, Charbonnier L-M, McMasters RL, Chatila T, Bleesing JJ. CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder. J Allergy Clin Immunol. 2017;140(3):862-864.e4.
14. Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M. Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis. Pediatr Blood Cancer. 2018;65(4).
15. Fernández KS, Antony R, Kumar A. Patients with" ALPS-like phenotype" diagnosed with immune dysregulation due to LRBA deficiency. Pediatr Blood Cancer. 2019;66(3):e27558.
16. Barzaghi F, Minniti F, Mauro M, Bortoli MD, Balter R, Bonetti E, et al. ALPS-like phenotype caused by ADA2 deficiency rescued by allogeneic hematopoietic stem cell transplantation. Front Immunol. 2019;9:2767.
17. Cagdas D, Halaçlı SO, Tan Ç, Lo B, Çetinkaya PG, Esenboğa S, et al. A spectrum of clinical findings from ALPS to CVID: several novel LRBA defects. J Clin Immunol. 2019;39(7):726-738.
18. Schipp C, Schlütermann D, Hönscheid A, Nabhani S, Höll J, Oommen PT, et al. EBV negative lymphoma and autoimmune lymphoproliferative syndrome like phenotype extend the clinical spectrum of primary immunodeficiency caused by STK4 deficiency. Front Immunol. 2018;9:2400.
19. Mao H, Yang W, Latour S, Yang J, Winter S, Zheng J, et al. RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. J Allergy Clin Immunol. 2018;142(2):595-604.e16.
20. Takagi M, Hoshino A, Yoshida K, Ueno H, Imai K, Piao J, et al. Genetic heterogeneity of uncharacterized childhood autoimmune diseases with lymphoproliferation. Pediatr Blood Cancer. 2018;65(2).
21. Westermann-Clark E, Grossi A, Fioredda F, Giardino S, Cappelli E, Terranova P, et al. RAG deficiency with ALPS features successfully treated with TCRαβ/CD19 cell depleted haploidentical stem cell transplant. Clin Immunol. 2018;187:102-103.
22. Cohen JM, Sebire NJ, Harvey J, Gaspar HB, Cathy C, Jones A, et al. Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation. Blood. 2007;110(6):2209-14.
23. Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, et al. Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117-25.
24. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al. Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood. 2015;125(4):591-9.
25. Sharifinejad N, Azizi G, Behniafard N, Zaki-Dizaji M, Jamee M, Yazdani R, et al. Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature. Immunol Invest. 2020;13:1-12.
26. Snow AL, Xiao W, Stinson JR, Lu W, Chaigne-Delalande B, Zheng L, et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutationsGermline CARD11 mutations in humans. J Exp Med. 2012;209(12):2247-61.
27. Gupta M, Aluri J, Desai M, Lokeshwar M, Taur P, Lenardo M, et al. Clinical, immunological, and molecular findings in four cases of B cell expansion with NF-κB and T cell anergy disease for the first time from India. Front Immunol. 2018;9:1049.
28. Outinen T, Syrjanen J, Rounioja S, Saarela J, Kaustio M, Helminen M. Constant B cell lymphocytosis since early age in a patient with CARD11 mutation: a 20-year follow-up. Clin Immunol. 2016;165:19-20.
29. Comrie WA, Faruqi AJ, Price S, Zhang Y, Rao VK, Su HC, et al. RELA haploinsufficiency in CD4 lymphoproliferative disease with autoimmune cytopenias. J Allergy Clin Immunol. 2018;141(4):1507-1510.e8.
30. Saettini F, Pelagatti M, Sala D, Moratto D, Giliani S, Badolato R, et al. Early diagnosis of PI3Kδ syndrome in a 2 years old girl with recurrent otitis and enlarged spleen. Immunol Lett. 2017;190:279-281.
31. Matson DR, Yang DT. Autoimmune Lymphoproliferative Syndrome: An Overview. Arch Pathol Lab Med. 2020;144(2):245-251.
32. Leal-Seabra F, Costa GS, Coelho HP, Oliveira A. Unexplained lymphadenopathies: autoimmune lymphoproliferative syndrome in an adult patient. BMJ Case Rep. 2016;2016:bcr2016216758.
33. Bride K, Teachey D. Autoimmune lymphoproliferative syndrome: more than a FAScinating disease. F1000Res. 2017;6:1928.
34. Shah S, Wu E, Rao VK, Tarrant TK. Autoimmune Lymphoproliferative Syndrome: an Update and Review of the Literature. Curr Allergy Asthma Rep. 2014;14(9):462.
35. Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L, et al. A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. Blood. 2011;118(18):4798-807.
36. Dowdell KC, Niemela JE, Price S, Davis J, Hornung RL, Oliveira JB, et al. Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome. Blood. 2010;115(25):5164-9.
37. Teachey DT, Seif AE, Grupp SA. Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). Br J Haematol. 2010;148(2):205-16.
| Files | ||
| Issue | Vol 4, No 2 (2021) | |
| Section | Review Article | |
| DOI | https://doi.org/10.18502/igj.v4i2.9983 | |
| Keywords | ||
| Primary Immunodeficiency ALPS Autoimmune Lymphoproliferative Like Syndrome Lymphoproliferation Autoimmunity LRBA STAT3 | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Nirouei M, Hafezi N, Rasouli SE. Monogenic Disorder Associated with Autoimmune Lymphoproliferative Syndrome-Like Phenotype: A Systematic Review. Immunol Genet J. 2021;4(2):76-86.
