Hematologic Problems in Hyper-IgM Patients
Abstract
Background/objectives: Hyper IgM (HIGM) syndrome is a rare kind of primary Immunodeficiency disease (PID) characterized by normal to the increased serum IgM and very low or undetectable IgG, IgA, and IgE. Broad spectrum of clinical manifestations and laboratory findings are observed in the HIGM patients including hematologic problem and malignancy. This study was conducted to assess demographic data, clinical manifestation, and immunological findings in the HIGM patients.
Methods: Lab findings and clinical presentations data of 79 Iranian patients diagnosed with HIgM syndrome were collected. All the patients were classified into two different groups including the patients with hematological problems and those without hematological problems.
Results: Hematologic problems were observed in 34 patients (43%, 23 males and 11 females). The most common hematologic problems types were anemia and leukemia (33 and 25%, respectively). Also, 19 patients (24.1%) had a family history of PID. Significant data that were higher in the patients with hematologic problems, were the oral ulcer (p=0.037), failure to thrive (p=0.022), recurrent diarrhoea (p=0.021), chronic diarrhoea (p=0.022), urinary tract infections (p=0.037), anemia (p=0.000), neutropenia (p=0.000), thrombocytopenia (p=0.001), gastrointestinal problem (p=0.011), neurologic problem (p=0.000), multiple site problem (p=0.000), platelet count (p=0.005), and IgG level (p=0.048).
Conclusion: The association between HIgM syndrome and hematologic problems could lead to severe clinical disorders. Therefore, it is necessary for immunologists to be aware of these situations.
1. Notarangelo LD, Duse M, Ugazio AGJIr. Im-munodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101-21.
2. Qamar N, Fuleihan RLJCria. The hyper IgM syndromes. Clin Rev Allergy Immunol. 2014;46(2):120-30.
3. Günaydin NC, Chou J, Karaca NE, Aksu G, Massaad MJ, Azarsiz E, et al. A novel diseasecausing CD40L mutation reduces expression of CD40 ligand, but preserves CD40 binding capacity. J Clin Immunol. . 2014;153(2):288-91.
4. Rosen FS, Kevy SV, Merler E, Janeway CA, Gitlin D. Recurrent bacterial infections and dysgamma-globulinemia: deficiency of 7S gammaglobulins in the presence of elevated 19S gamma- globulins. Report of two cases. Pediatrics. 1961;28:182-95.
5. Yazdani R, Fekrvand S, Shahkarami S, Azizi G, Moazzami B, Abolhassani H, et al. The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clin Immunol. 2018;198: 19-30 6. Fuleihan R, Ramesh N, Loh R, Jabara H, Rosen RS, Chatila T, et al. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A. 1993;90(6):2170-3.
7. Aghamohammadi A, Mohammadinejad P, Abolhassani H, Mirminachi B, Movahedi M, Gharagozlou M, et al. Primary immunodeficiency disorders in Iran: update and new insights from the third report of the national registry. J Clin Immunol. 2014;34(4):478- 90.
8. Azizi G, Abolhassani H, Asgardoon MH, Rahnavard J, Dizaji MZ, Yazdani R, et al. The use of Immunoglobulin Therapy in Primary Immunodeficiency Diseases. Endocrine, metabolic & immune disorders drug targets. Endocr Metab Immune Disord Drug Targets. 2016;16(2):80-8.
9. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3- kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606. e4.
10. Kitchen BJ, Boxer LA. Large granular lymphocyte leukemia (LGL) in a child with Hyper IgM syndrome and autoimmune hemolytic anemia. Pediatr blood & cancer. 2008;50(1):142-5.
11. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B- cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
12. Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53(9):575-90.
13. Verhoeven D, Stoppelenburg AJ, Meyer- Wentrup F, Boes M. Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy. Clin Immunol. 2018;190:22-31.
14. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant- activating germline mutations in the gene encoding the PI (3) K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88.
15. Crank M, Grossman J, Moir S, Pittaluga S, Buckner C, Kardava L, et al. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J clin immuno. 2014;34(3):272-6.
16. Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(4):1398-403.
17. Xing Y, Hogge DE. Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110δ subunit and mitogen-extracellular activated pro-tein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors. Leuk Res. 2013;37(6):697-704.
18. Seiler T, Hutter G, Dreyling M. The emerging role of PI3K inhibitors in the treatment of hematological malignancies: preclinical data and clinical progress to date. Drugs. 2016;76(6):639-46.
19. Hervé M, Isnardi I, Ng Y-s, Bussel JB, Ochs HD, Cunningham-Rundles C, et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med. 2007;204(7):1583-93.
20. Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr.1997;131(1):47-54.
21. Notarangelo L, Hayward A. X-linked immunodeficiency with hyper-IgM (XHIM). Clin Exp Immunol.2000;120(3):399-405.
22. Durandy A, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev. 2005;203(1):67-79.
23. Pessach IM, Notarangelo LD. X-linked primary immunodeficiencies as a bridge to better understandingX-chromosome related autoimmunity.J Autoimmun. 2009;33(1):17-24.
24. Quartier P, Bustamante J, Sanal O, Plebani A, Debré M, Deville A, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency. Clin immunol. 2004;110(1):22-9.
25. Ouadani H, Ben-Mustapha I, Ben-Ali M, Ben-Khemis L, Larguèche B, Boussoffara R, et al. Novel and recurrent AID mutations underlie prevalent autosomal recessive form of HIGM in consanguineous patients. Immunogenetics. 2016;68(1):19-28.
26. Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X- linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine. 2003;82(6):373-84.
27. McGhee SA. Hyper-IgM Syndrome (HIGM). Chronic Complex Diseases of Childhood: A Practical Guide for Clinicians; 2011. 300 p.
28. Orange JS, Levy O, Geha RS. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-κB activation. Immunol Rev. 2005;203(1):21-37.
29. Rezaei N, Farhoudi A, Pourpak Z, Aghamohammadi A, Moin M, Gharagozlou M, et al. Neutropenia in patients with primary antibody deficiency disorders. Iran J Allergy Asthma Immunol; 2004. p. 77-82.
30. Cham B, Bonilla MA, Winkelstein J, editors. Neutropenia associated with primary immunodeficiency syndromes. Seminars in hematology. 2002;39(2): 107-112 31. Ming JE, Stiehm ER, Graham J, John M. Syndromic immunodeficiencies: genetic syndromes associated with immune abnormalities. Crit Rev Cl Lab Sci. 2003;40(6):587-642.
32. Richard Lee G, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers G. Wintrobe’s clinical hematology. Williams & Wilkins, Baltimore; 2003.
33. Kutukculer N, Moratto D, Aydinok Y, Lougaris V, Aksoylar S, Plebani A, et al. Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J Pediatr. 2003;142(2):194-6.
34. Constantinou CL. Differential diagnosis of neutropenia. Primary Hematology: Springer; 2001. p. 93-104.
35. Klaudel-Dreszler M, Bernatowska E. Chronic neutropenia in children-diagnostics, therapeutic management and prophylaxis. Central European Journal of Immunology. 2007;32(4):226.
36. Nabavi M, Arshi S, Bemanian M, Aghamohammadi A, Mansouri D, Hedayat M, et al. Long-term follow-up of ninety eight Iranian patients with primary immune deficiency in a single tertiary centre. Allergol Immunopathol. 2016;44(4):322-30.
37. Mohammadinejad P, Pourhamdi S, Abolhassani H, Mirminachi B, Havaei A, Masoom S, et al. Primary antibody deficiency in a tertiary referral hospital: a 30-year experiment. J Investig Allergol Clin Immunol. 2015;25(6):416-25.
38. Ghiasy S, Parvaneh L, Azizi G, Sadri G, Zaki dizaji M, Abolhassani H, et al. The clinical significance of complete class switching defect in Ataxia telangiectasia patients. Expert Rev Clin Immunol. 2017;13(5):499-505.
39. Noordzij JG, Wulffraat N, Haraldsson Á, Meyts I, van’t Veer L, Hogervorst F, et al. Ataxia–telangiectasia patients presenting with hyper-IgM syndrome. Arch Dis Child. 2009;94(6):448-9.
40. Aschermann Z, Gomori E, Kovacs GG, Pal E, Simon G, Komoly S, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. 2007;64(2):273-6.
2. Qamar N, Fuleihan RLJCria. The hyper IgM syndromes. Clin Rev Allergy Immunol. 2014;46(2):120-30.
3. Günaydin NC, Chou J, Karaca NE, Aksu G, Massaad MJ, Azarsiz E, et al. A novel diseasecausing CD40L mutation reduces expression of CD40 ligand, but preserves CD40 binding capacity. J Clin Immunol. . 2014;153(2):288-91.
4. Rosen FS, Kevy SV, Merler E, Janeway CA, Gitlin D. Recurrent bacterial infections and dysgamma-globulinemia: deficiency of 7S gammaglobulins in the presence of elevated 19S gamma- globulins. Report of two cases. Pediatrics. 1961;28:182-95.
5. Yazdani R, Fekrvand S, Shahkarami S, Azizi G, Moazzami B, Abolhassani H, et al. The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. Clin Immunol. 2018;198: 19-30 6. Fuleihan R, Ramesh N, Loh R, Jabara H, Rosen RS, Chatila T, et al. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A. 1993;90(6):2170-3.
7. Aghamohammadi A, Mohammadinejad P, Abolhassani H, Mirminachi B, Movahedi M, Gharagozlou M, et al. Primary immunodeficiency disorders in Iran: update and new insights from the third report of the national registry. J Clin Immunol. 2014;34(4):478- 90.
8. Azizi G, Abolhassani H, Asgardoon MH, Rahnavard J, Dizaji MZ, Yazdani R, et al. The use of Immunoglobulin Therapy in Primary Immunodeficiency Diseases. Endocrine, metabolic & immune disorders drug targets. Endocr Metab Immune Disord Drug Targets. 2016;16(2):80-8.
9. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3- kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606. e4.
10. Kitchen BJ, Boxer LA. Large granular lymphocyte leukemia (LGL) in a child with Hyper IgM syndrome and autoimmune hemolytic anemia. Pediatr blood & cancer. 2008;50(1):142-5.
11. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B- cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
12. Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53(9):575-90.
13. Verhoeven D, Stoppelenburg AJ, Meyer- Wentrup F, Boes M. Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy. Clin Immunol. 2018;190:22-31.
14. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant- activating germline mutations in the gene encoding the PI (3) K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88.
15. Crank M, Grossman J, Moir S, Pittaluga S, Buckner C, Kardava L, et al. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J clin immuno. 2014;34(3):272-6.
16. Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA, et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(4):1398-403.
17. Xing Y, Hogge DE. Combined inhibition of the phosphoinosityl-3-kinase (PI3Kinase) P110δ subunit and mitogen-extracellular activated pro-tein kinase (MEKinase) shows synergistic cytotoxicity against human acute myeloid leukemia progenitors. Leuk Res. 2013;37(6):697-704.
18. Seiler T, Hutter G, Dreyling M. The emerging role of PI3K inhibitors in the treatment of hematological malignancies: preclinical data and clinical progress to date. Drugs. 2016;76(6):639-46.
19. Hervé M, Isnardi I, Ng Y-s, Bussel JB, Ochs HD, Cunningham-Rundles C, et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med. 2007;204(7):1583-93.
20. Levy J, Espanol-Boren T, Thomas C, Fischer A, Tovo P, Bordigoni P, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr.1997;131(1):47-54.
21. Notarangelo L, Hayward A. X-linked immunodeficiency with hyper-IgM (XHIM). Clin Exp Immunol.2000;120(3):399-405.
22. Durandy A, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev. 2005;203(1):67-79.
23. Pessach IM, Notarangelo LD. X-linked primary immunodeficiencies as a bridge to better understandingX-chromosome related autoimmunity.J Autoimmun. 2009;33(1):17-24.
24. Quartier P, Bustamante J, Sanal O, Plebani A, Debré M, Deville A, et al. Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to activation-induced cytidine deaminase deficiency. Clin immunol. 2004;110(1):22-9.
25. Ouadani H, Ben-Mustapha I, Ben-Ali M, Ben-Khemis L, Larguèche B, Boussoffara R, et al. Novel and recurrent AID mutations underlie prevalent autosomal recessive form of HIGM in consanguineous patients. Immunogenetics. 2016;68(1):19-28.
26. Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, et al. The X- linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine. 2003;82(6):373-84.
27. McGhee SA. Hyper-IgM Syndrome (HIGM). Chronic Complex Diseases of Childhood: A Practical Guide for Clinicians; 2011. 300 p.
28. Orange JS, Levy O, Geha RS. Human disease resulting from gene mutations that interfere with appropriate nuclear factor-κB activation. Immunol Rev. 2005;203(1):21-37.
29. Rezaei N, Farhoudi A, Pourpak Z, Aghamohammadi A, Moin M, Gharagozlou M, et al. Neutropenia in patients with primary antibody deficiency disorders. Iran J Allergy Asthma Immunol; 2004. p. 77-82.
30. Cham B, Bonilla MA, Winkelstein J, editors. Neutropenia associated with primary immunodeficiency syndromes. Seminars in hematology. 2002;39(2): 107-112 31. Ming JE, Stiehm ER, Graham J, John M. Syndromic immunodeficiencies: genetic syndromes associated with immune abnormalities. Crit Rev Cl Lab Sci. 2003;40(6):587-642.
32. Richard Lee G, Foerster J, Lukens J, Paraskevas F, Greer JP, Rodgers G. Wintrobe’s clinical hematology. Williams & Wilkins, Baltimore; 2003.
33. Kutukculer N, Moratto D, Aydinok Y, Lougaris V, Aksoylar S, Plebani A, et al. Disseminated cryptosporidium infection in an infant with hyper-IgM syndrome caused by CD40 deficiency. J Pediatr. 2003;142(2):194-6.
34. Constantinou CL. Differential diagnosis of neutropenia. Primary Hematology: Springer; 2001. p. 93-104.
35. Klaudel-Dreszler M, Bernatowska E. Chronic neutropenia in children-diagnostics, therapeutic management and prophylaxis. Central European Journal of Immunology. 2007;32(4):226.
36. Nabavi M, Arshi S, Bemanian M, Aghamohammadi A, Mansouri D, Hedayat M, et al. Long-term follow-up of ninety eight Iranian patients with primary immune deficiency in a single tertiary centre. Allergol Immunopathol. 2016;44(4):322-30.
37. Mohammadinejad P, Pourhamdi S, Abolhassani H, Mirminachi B, Havaei A, Masoom S, et al. Primary antibody deficiency in a tertiary referral hospital: a 30-year experiment. J Investig Allergol Clin Immunol. 2015;25(6):416-25.
38. Ghiasy S, Parvaneh L, Azizi G, Sadri G, Zaki dizaji M, Abolhassani H, et al. The clinical significance of complete class switching defect in Ataxia telangiectasia patients. Expert Rev Clin Immunol. 2017;13(5):499-505.
39. Noordzij JG, Wulffraat N, Haraldsson Á, Meyts I, van’t Veer L, Hogervorst F, et al. Ataxia–telangiectasia patients presenting with hyper-IgM syndrome. Arch Dis Child. 2009;94(6):448-9.
40. Aschermann Z, Gomori E, Kovacs GG, Pal E, Simon G, Komoly S, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. 2007;64(2):273-6.
| Files | ||
| Issue | Vol 3, No 1 (2020) | |
| Section | Original Article | |
| DOI | https://doi.org/10.22034/igj.2020.224457.1033 | |
| Keywords | ||
| hyper IgM hematologic problems primary immunodeficiency disorders malignancy | ||
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How to Cite
1.
Sohani M, Pashangzadeh S. Hematologic Problems in Hyper-IgM Patients. Immunol Genet J. 2020;3(1):15-28.
