Human inborn errors of immunity: diagnosis and management

Abstract

Primary immunodeficiency disease (PID) now known as inborn errors of immunity (IEI) is genetic disorder(s) that impair the immune system. IEI is a heterogeneous group of diseases of more than 485 lifelong genetic disorders mainly due to intrinsic defect(s) in human immune system. Adults, children, and neonates can be affected by IEI diseases. The first IEI defects were reported in the 1950s, but Bruton’s use of immunoglobulin in 1952 to treat an 8-year-old boy suffering from pneumonia and other bacterial sino-pulmonary infections brought the PID or IEI and associated diseases into limelight. This review will focus on a general description of IEI (history, epidemiology, pathophysiology, and diagnosis), inborn errors of metabolism, and the management (cure or therapy) of IEI diseases.

Keywords

Primary immunodeficiency disease / inborn errors of immunity / classification of inborn errors of immunity by International Union of Immunological Societies / in born error of metabolism / diagnosis and management of inborn errors of immunity

References

[1] Ochs HD, Hagin D. Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment. Ann Allergy Asthma Immunol. 2014; 112: 489-95. [DOI] [PubMed]

[2] Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022; 42: 1473-507. [DOI] [PubMed] [PMC]

[3] Gray PE, David C. Inborn Errors of Immunity and Autoimmune Disease. J Allergy Clin Immunol Pract. 2023; 11: 1602-22. [DOI] [PubMed]

[4] Imbach P, Barandun S, d’Apuzzo V, Baumgartner C, Hirt A, Morell A, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981; 1: 1228-31. [DOI] [PubMed]

[5] Ouwehand WH, Smith G, Ranasinghe E. Management of severe alloimmune thrombocytopenia in the newborn. Arch Dis Child Fetal Neonatal Ed. 2000; 82: F173-5. [DOI] [PubMed] [PMC]

[6] Kebudi R, Kiykim A, Sahin MK. Primary Immunodeficiency and Cancer in Children; A Review of the Literature. Curr Pediatr Rev. 2019; 15: 245-50. [DOI] [PubMed] [PMC]

[7] Yel L. Selective IgA deficiency. J Clin Immunol. 2010; 30: 10-6. [DOI] [PubMed] [PMC]

[8] Notarangelo LD, Bacchetta R, Casanova J, Su HC. Human inborn errors of immunity: An expanding universe. Sci Immunol. 2020; 5: eabb1662. [DOI] [PubMed] [PMC]

[9] Moratti M, Conti F, Giannella M, Ferrari S, Borghesi A. How to: Diagnose inborn errors of intrinsic and innate immunity to viral, bacterial, mycobacterial, and fungal infections. Clin Microbiol Infect. 2022; 28: 1441-8. [DOI] [PubMed]

[10] Hall MJ, Bernhisel R, Hughes E, Larson K, Rosenthal ET, Singh NA, et al. Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers . Cancer Prev Res (Phila). 2021; 14: 433-40. [DOI] [PubMed] [PMC]

[11] Delavari S, Wang Y, Shad TM, Pashangzadeh S, Nazari F, Salami F, et al. Clinical and Immunologic Characteristics of Non-Hematologic Cancers in Patients with Inborn Errors of Immunity. Cancers (Basel). 2023; 15: 764. [DOI] [PubMed] [PMC]

[12] Delavari S, Rasouli SE, Fekrvand S, Chavoshzade Z, Mahdaviani SA, Shirmast P, et al. Clinical heterogeneity in families with multiple cases of inborn errors of immunity. Clin Immunol. 2024; 259: 109896. [DOI] [PubMed]

[13] Cheng J, Saldaña BJD, Chandrakasan S, Keller M. Pediatric lymphoproliferative disorders associated with inborn errors of immunity. Clin Immunol. 2024; 266: 110332. [DOI] [PubMed]

[14] Janeway CA, Craig J, Davidson M, Downey W, Gitlin D, Sullivan JC, et al. Hypergammaglobulinemia associated with severe recurrent and chronic nonspecific infection. Am J Dis Child. 1954; 88: 388-92.

[15] Glanzmann E, Riniker P. Essential lymphocytophthisis; new clinical aspect of infant pathology. Ann Paediatr. 1950; 175: 1-32. [PubMed]

[16] Bruton OC. Agammaglobulinemia. Pediatrics. 1952; 9: 722-8. [PubMed]

[17] Casanova J, Abel L. Lethal Infectious Diseases as Inborn Errors of Immunity: Toward a Synthesis of the Germ and Genetic Theories. Annu Rev Pathol. 2021; 16: 23-50. [DOI] [PubMed] [PMC]

[18] Akalu YT, Bogunovic D. Inborn errors of immunity: an expanding universe of disease and genetic architecture. Nat Rev Genet. 2024; 25: 184-95. [DOI] [PubMed]

[19] Moazzen N, Ahanchian H, Aelami MH, Asiyon H, Astaneh M, Naeimi AM, et al. COVID-19 in children with inborn errors of immunity: clinical scenarios. Am J Clin Exp Immunol. 2021; 10: 77-85. [PubMed] [PMC]

[20] Staels F, Collignon T, Betrains A, Gerbaux M, Willemsen M, Humblet-Baron S, et al. Monogenic Adult-Onset Inborn Errors of Immunity. Front Immunol. 2021; 12: 753978. [DOI] [PubMed] [PMC]

[21] Yu JE. New primary immunodeficiencies 2023 update. Curr Opin Pediatr. 2024; 36: 112-23. [DOI] [PubMed]

[22] Immune Deficiency Foundation. Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency Diseases. 3rd ed. Hanove: Immune Deficiency Foundation ; 2015.

[23] Wood P, Stanworth S, Burton J, Jones A, Peckham DG, Green T, et al. Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: a systematic review. Clin Exp Immunol. 2007; 149: 410-23. [DOI] [PubMed] [PMC]

[24] Costagliola G, Peroni DG, Consolini R. Beyond Infections: New Warning Signs for Inborn Errors of Immunity in Children. Front Pediatr. 2022; 10: 855445. [DOI] [PubMed] [PMC]

[25] Approach to the Patient With Suspected Immunodeficiency [Internet]. Rahway: Merck & Co., Inc., Rahway, NJ, USA and its affiliates; [cited 2024 Nov 15]. Available from: https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/approach-to-the-patient-with-suspected-immunodeficiency

[26] Understanding Primary immunodeficiency (diagnosis) [Internet]. Hanover: Immune Deficiency Foundation; [cited 2024 Nov 20]. https://primaryimmune.org/understanding-primary-immunodeficiency/diagnosis/laboratory-tests

[27] King DJ. Applications And Engineering Of Monoclonal Antibodies. 1st ed. London: CRC Press; 1998. [DOI]

[28] Gajl-Peczalska K, Lim SD, Good RA. B lymphocytes in primary and secondary deficiencies of humoral immunity. Birth Defects Orig Artic Ser. 1975; 11: 33-5. [PubMed]

[29] Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies (1). N Engl J Med. 1984; 311: 235-42. [DOI] [PubMed]

[30] Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies. (2). N Engl J Med. 1984; 311: 300-10. [DOI] [PubMed]

[31] Sirianni MC, Fiorilli M, Pandolfi F, Quinti I, Aiuti F. Natural killer activity and lymphocyte subpopulations in patients with primary humoral and cellular immunodeficiencies. Clin Immunol Immunopathol. 1981; 21: 12-9. [DOI] [PubMed]

[32] Aiuti F, Pandolfi F, Fiorilli M, Bonomo R, Quinti I, Frielingsdorf A, et al. Monoclonal antibody analysis of T cell subsets in 40 patients with immunodeficiencies. J Clin Immunol. 1982; 2: 81S-9S. [PubMed]

[33] Buckley RH, Gard S, Schiff RI, Sampson HA. T cells and T-cell subsets in a large population of patients with primary immunodeficiency. Birth Defects Orig Artic Ser. 1983; 19: 187-91. [PubMed]

[34] Aiuti F, Quinti I, Seminara R, Sirianni MC, Vierucci A, Abo T, et al. Usefulness of monoclonal antibodies in the diagnosis and monitoring of patients with primary immunodeficiencies: combined experience in three clinical immunology centers. Diagn Immunol. 1983; 1: 188-94. [PubMed]

[35] Peter HH, Friedrich W, Dopfer R, Müller W, Kortmann C, Pichler WJ, et al. NK cell function in severe combined immunodeficiency (SCID): evidence of a common T and NK cell defect in some but not all SCID patients. J Immunol. 1983; 131: 2332-9. [PubMed]

[36] Tedder TF, Crain MJ, Kubagawa H, Clement LT, Cooper MD. Evaluation of lymphocyte differentiation in primary and secondary immunodeficiency diseases. J Immunol. 1985; 135: 1786-91. [PubMed]

[37] Hsu AP, Holland SM. Host genetics of innate immune system in infection. Curr Opin Immunol. 2022; 74: 140-9. [DOI] [PubMed]

[38] Pinto-Mariz F, Goudouris E. Inborn Errors of Immunity: What to Look for Beyond Infections. Immunological Sci. 2021; 5: 15-21.

[39] Kitcharoensakkul M, Cooper MA. Rheumatologic and autoimmune manifestations in primary immune deficiency. Curr Opin Allergy Clin Immunol. 2019; 19: 545-52. [DOI] [PubMed]

[40] Chan SK, Gelfand EW. Primary Immunodeficiency Masquerading as Allergic Disease. Immunol Allergy Clin North Am. 2015; 35: 767-78. [DOI] [PubMed]

[41] Havnaer A, Han G. Autoinflammatory Disorders: A Review and Update on Pathogenesis and Treatment. Am J Clin Dermatol. 2019; 20: 539-64. [DOI] [PubMed]

[42] Bomken S, van der Werff Ten Bosch J, Attarbaschi A, Bacon CM, Borkhardt A, Boztug K, et al. Current Understanding and Future Research Priorities in Malignancy Associated With Inborn Errors of Immunity and DNA Repair Disorders: The Perspective of an Interdisciplinary Working Group. Front Immunol. 2018; 9: 2912. [DOI] [PubMed] [PMC]

[43] Condino-Neto A, Espinosa-Rosales FJ. Changing the Lives of People With Primary Immunodeficiencies (PI) With Early Testing and Diagnosis. Front Immunol. 2018; 9: 1439. [DOI] [PubMed] [PMC]

[44] King JR, Hammarström L. Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice. J Clin Immunol. 2018; 38: 56-66. [DOI] [PubMed] [PMC]

[45] Grumach AS, Goudouris ES. Inborn Errors of Immunity: how to diagnose them? J Pediatr (Rio J). 2021; 97 Suppl 1: S84-90. [DOI] [PubMed] [PMC]

[46] Chinen J, Paul M, Shearer W. Approach to the Evaluation of the Patient With Suspected Immunodeficiency. Clin Immunol. 2019; 451-61. [DOI]

[47] Rosenzweig SD, Kobrynski L, Fleisher TA. Laboratory evaluation of primary immunodeficiency disorders. In: Sullivan K, Stiehm E, editors. Stiehm’s Immune Deficiencies: inborn errors of immunity. 2nd ed. London: Elsevier Inc.; 2020.

[48] Ramirez-Alejo N, Santos-Argumedo L. Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella. J Interferon Cytokine Res. 2014; 34: 307-17. [DOI] [PubMed] [PMC]

[49] El-Hattab AW. Inborn errors of metabolism. Clin Perinatol. 2015; 42: 413-39, x. [DOI] [PubMed]

[50] Campeau PM, Scriver CR, Mitchell JJ. A 25-year longitudinal analysis of treatment efficacy in inborn errors of metabolism. Mol Genet Metab. 2008; 95: 11-6. [DOI] [PubMed]

[51] Saudubray J, Mochel F, Lamari F, Garcia-Cazorla A. Proposal for a simplified classification of IMD based on a pathophysiological approach: A practical guide for clinicians. J Inherit Metab Dis. 2019; 42: 706-27. [DOI] [PubMed]

[52] Leonard JV, Morris AA. Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr. 2006; 95: 6-14. [DOI] [PubMed]

[53] Chakrapani A, Cleary MA, Wraith JE. Detection of inborn errors of metabolism in the newborn. Arch Dis Child Fetal Neonatal Ed. 2001; 84: F205-10. [DOI] [PubMed] [PMC]

[54] Jeanmonod R, Asuka E, Jeanmonod D. Inborn Errors of Metabolism. Treasure Island (FL): StatPearls Publishing; 2025.

[55] Inborn Errors of Metabolism (IEM) [Internet]. Cleveland: Cleveland Clinic.; c2025 [2024 Dec 10]. Available from: https://my.clevelandclinic.org/health/diseases/17962-inherited-metabolic-disorders

[56] Solares I, Heredia-Mena C, Castelbón FJ, Jericó D, Córdoba KM, Fontanellas A, et al. Diagnosis and Management of Inborn Errors of Metabolism in Adult Patients in the Emergency Department. Diagnostics (Basel). 2021; 11: 2148. [DOI] [PubMed] [PMC]

[57] Phenylketonuria (PKU) [Internet]. Mayo Foundation for Medical Education and Research (MFMER); [cited 2025 Jan 5]. Available from: https://www.mayoclinic.org/diseases-conditions/phenylketonuria/symptoms-causes/syc-20376302

[58] Úbeda F, Santander S, Luesma MJ. Clinical Practice Guidelines for the Diagnosis and Management of Hereditary Fructose Intolerance. Diseases. 2024; 12: 44. [DOI] [PubMed] [PMC]

[59] Ribas GS, Vargas CR. Evidence that Oxidative Disbalance and Mitochondrial Dysfunction are Involved in the Pathophysiology of Fatty Acid Oxidation Disorders. Cell Mol Neurobiol. 2022; 42: 521-32. [DOI] [PubMed] [PMC]

[60] Bennett MJ. Pathophysiology of fatty acid oxidation disorders. J Inherit Metab Dis. 2010; 33: 533-7. [DOI] [PubMed]

[61] Jaeken J, Carchon H. The carbohydrate-deficient glycoprotein syndromes: an overview. J Inherit Metab Dis. 1993; 16: 813-20. [DOI] [PubMed]

[62] Kruszka P, Regier D. Inborn Errors of Metabolism: From Preconception to Adulthood. Am Fam Physician. 2019; 99: 25-32. [PubMed]

[63] Gray RG, Preece MA, Green SH, Whitehouse W, Winer J, Green A. Inborn errors of metabolism as a cause of neurological disease in adults: an approach to investigation. J Neurol Neurosurg Psychiatry. 2000; 69: 5-12. [DOI] [PubMed] [PMC]

[64] Maksoud MA, ELsayed SM, Shatla RH, Imam AA, Elsayed RM, Mosabah AA, et al. Frequency of inborn errors of metabolism screening for children with unexplained acute encephalopathy at an emergency department. Neuropsychiatr Dis Treat. 2018; 14: 1715-20. [DOI] [PubMed] [PMC]

[65] Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998; 102: E69. [DOI] [PubMed]

[66] Spencer M. Neonatal Grand Rounds, University of Florida. American Society of Health-System Pharmacists; 2017.

[67] Arnold GL. Inborn errors of metabolism in the 21^st century: past to present . Ann Transl Med. 2018; 6: 467. [DOI] [PubMed] [PMC]

[68] Li H, Byers HM, Diaz-Kuan A, Vos MB, Hall PL, Tortorelli S, et al. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab. 2018; 123: 428-32. [DOI] [PubMed]

[69] Merritt JL 2nd, Norris M, Kanungo S. Fatty acid oxidation disorders. Ann Transl Med. 2018; 6: 473. [DOI] [PubMed] [PMC]

[70] Sacco KA, Stack M, Notarangelo LD. Targeted pharmacologic immunomodulation for inborn errors of immunity. Br J Clin Pharmacol. 2022; 88: 2500-8. [DOI] [PubMed]

[71] Paris K, Wall LA. The Treatment of Primary Immune Deficiencies: Lessons Learned and Future Opportunities. Clin Rev Allergy Immunol. 2023; 65: 19-30. [DOI] [PubMed] [PMC]

[72] Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136: 1186-205.e1. [DOI] [PubMed]

[73] Ballow M, Paris K, de la Morena M. Should Antibiotic Prophylaxis Be Routinely Used in Patients with Antibody-Mediated Primary Immunodeficiency? J Allergy Clin Immunol Pract. 2018; 6: 421-6. [DOI] [PubMed]

[74] Paccoud O, Warris A, Puel A, Lanternier F. Inborn errors of immunity and invasive fungal infections: presentation and management. Curr Opin Infect Dis. 2024; 37: 464-73. [DOI] [PubMed]

[75] Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med. 1993; 86: 31-42. [PubMed]

[76] Peter JG, Chapel H. Immunoglobulin replacement therapy for primary immunodeficiencies. Immunotherapy. 2014; 6: 853-69. [DOI] [PubMed]

[77] Frazer JK, Capra JD. Immunoglobulins Structure and Function. In: Fundamental immunology. 4th ed. Philadelphia: Lippincott-Raven; 1999. pp. 37-74.

[78] Penichet ML, Morrison SL. Design and engineering human forms of monoclonal antibodies. Drug Dev Res. 2004; 61: 121-36.

[79] Jolles S, Orange JS, Gardulf A, Stein MR, Shapiro R, Borte M, et al. Current treatment options with immunoglobulin G for the individualization of care in patients with primary immunodeficiency disease. Clin Exp Immunol. 2015; 179: 146-60. [DOI] [PubMed] [PMC]

[80] Roskos LK, Davis CG, Schwab GM. The clinical pharmacology of therapeutic monoclonal antibodies. Drug Dev Res. 2004; 61: 108-20.

[81] Mahmood I, Green MD. Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin Pharmacokinet. 2005; 44: 331-47. [DOI] [PubMed]

[82] FDA. Guidance for Industry: Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency. U.S. Department of Health and Human Services Food and Drug Administration Center for Biologics Evaluation and Research; 2008.

[83] Lucas M, Lee M, Lortan J, Lopez-Granados E, Misbah S, Chapel H. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J Allergy Clin Immunol. 2010; 125: 1354-60.e4. [DOI] [PubMed]

[84] Yong PL, Boyle J, Ballow M, Boyle M, Berger M, Bleesing J, et al. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology. Clin Immunol. 2010; 135: 255-63. [DOI] [PubMed]

[85] Roifman CM, Berger M, Notarangelo LD. Management of primary antibody deficiency with replacement therapy: summary of guidelines. Immunol Allergy Clin North Am. 2008; 28: 875-6, x. [DOI] [PubMed]

[86] Rich AL, Jeune IRL, McDermott L, Kinnear WJM. Serial lung function tests in primary immune deficiency. Clin Exp Immunol. 2008; 151: 110-3. [DOI] [PubMed] [PMC]

[87] Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. 2008; 122: 210-2. [DOI] [PubMed]

[88] Newsome BW, Ernstoff MS. The clinical pharmacology of therapeutic monoclonal antibodies in the treatment of malignancy; have the magic bullets arrived? Br J Clin Pharmacol. 2008; 66: 6-19. [DOI] [PubMed] [PMC]

[89] Berger M, Jolles S, Orange JS, Sleasman JW. Bioavailability of IgG administered by the subcutaneous route. J Clin Immunol. 2013; 33: 984-90. [DOI] [PubMed] [PMC]

[90] Mahmood I, Li Z. Immunoglobulin therapies for primary immunodeficiency diseases (part 1): understanding the pharmacokinetics. Immunotherapy. 2024; 16: 879-94. [DOI] [PubMed] [PMC]

[91] Kerr J, Quinti I, Eibl M, Chapel H, Späth PJ, Sewell WAC, et al. Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe. Front Immunol. 2014; 5: 629. [DOI] [PubMed] [PMC]

[92] Koleba T, Ensom MHH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006; 26: 813-27. [DOI] [PubMed]

[93] Mahmood I, Tegenge MA, Golding B. Considerations for Optimizing Dosing of Immunoglobulins Based on Pharmacokinetic Evidence. Antibodies (Basel). 2020; 9: 24. [DOI] [PubMed] [PMC]

[94] Li Z, Mahmood I. Immunoglobulin therapies for primary immunodeficiency diseases (part 2): considerations for dosing strategies. Immunotherapy. 2024; 16: 895-905. [DOI] [PubMed] [PMC]

[95] Noya FJ, Rench MA, Courtney JT, Feldman S, Baker CJ. Pharmacokinetics of intravenous immunoglobulin in very low birth weight neonates. Pediatr Infect Dis J. 1989; 8: 759-63. [DOI] [PubMed]

[96] Weisman LE, Fischer GW, Marinelli P, Hemming VG, Pierce JR, Golden SM, et al. Pharmacokinetics of intravenous immunoglobulin in neonates. Vox Sang. 1989; 57: 243-8. [DOI] [PubMed]

[97] Mahmood I, Tegenge MA, Golding B. Considerations for pharmacokinetic assessment of immunoglobulins: Gammagard in very low birth weight neonates with and without baseline-correction. Int Immunopharmacol. 2020; 82: 106358. [DOI] [PubMed]

[98] Tegenge MA, Mahmood I. Population pharmacokinetics of immunoglobulin intravenous preparation in very low birth weight neonates. Int Immunopharmacol. 2020; 80: 106192. [DOI] [PubMed]

[99] Bruin LMOd, Lankester AC, Staal FJT. Advances in gene therapy for inborn errors of immunity. Curr Opin Allergy Clin Immunol. 2023; 23: 467-77. [DOI] [PubMed] [PMC]

[100] Laberko A, Sultanova E, Idarmacheva A, Skvortsova Y, Shelikhova L, Nechesnyuk A, et al. Second allogeneic hematopoietic stem cell transplantation in patients with inborn errors of immunity. Bone Marrow Transplant. 2023; 58: 273-81. [DOI] [PubMed] [PMC]

[101] Olsson R, Remberger M, Schaffer M, Berggren DM, Svahn B, Mattsson J, et al. Graft failure in the modern era of allogeneic hematopoietic SCT. Bone Marrow Transplant. 2013; 48: 537-43. [DOI] [PubMed]

[102] Wehr C, Gennery AR, Lindemans C, Schulz A, Hoenig M, Marks R, et al. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J Allergy Clin Immunol. 2015; 135: 988-97.e6. [DOI] [PubMed]

[103] Somekh I, Hendel A, Somech R. Evolution of Gene Therapy for Inborn Errors of Immunity. JAMA Pediatr. 2024; 178: 645-6. [DOI] [PubMed]

[104] Bak RO, Gomez-Ospina N, Porteus MH. Gene Editing on Center Stage. Trends Genet. 2018; 34: 600-11. [DOI] [PubMed]

[105] Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products . EMBO Mol Med. 2017; 9: 737-40. [DOI] [PubMed] [PMC]

[106] Gene therapy [Internet]. Mayo Foundation for Medical Education and Research (MFMER); c1998-2025 [cited 2025 Jan 15]. Available from: https://www.mayoclinic.org/tests-procedures/gene-therapy/about/pac-20384619

[107] Vienne Dd. What is a phenotype? History and new developments of the concept. Genetica. 2022; 150: 153-8. [DOI] [PubMed]

[108] What is Reverse Genetics? [Internet]. News-Medical.net; c2000-2025 [cited 2025 Jan 20]. Available from: https://www.news-medical.net/health/What-is-Reverse-Genetics.aspx

[109] What Is Gene Reversal? [Internet]. MedicineNet, Inc.; c1996- 2025 [cited 2025 Jan 20]. Available from: https://www.medicinenet.com/what_is_gene_reversal/article.htm

[110] ASCENIV (immune globulin intravenous, human-slra) [Internet]. RxList Inc.; c2025 [cited 2025 Jan 20]. Available from: https://www.rxlist.com/hiv_aids_myths_and_facts_slideshow_pictures/article.htm

[111] BIVIGAM Immune Globulin Intravenous (Human), 10% Liquid [Internet]. FDA; [cited 2025 Jan 21]. Available from: https://www.fda.gov/media/84782/download

[112] Flebogamma DIF 10% Immune Globulin Intravenous (Human) [Internet]. FDA; [cited 2025 Jan 21]. Available from: https://www.fda.gov/media/83042/download

[113] PANZYGA, (immune globulin intravenous, human - ifas) [Internet]. FDA; [cited 2025 Jan 21]. Available from: https://www.fda.gov/media/115397/download

[114] Privigen, Immune Globulin Intravenous (Human), 10% Liquid [Internet]. FDA; [cited 2025 Jan 21]. Available from: https://www.fda.gov/media/83304/download?attachment