Syndromic immunodeficiencies: a pediatrician’s perspective on selected diseases

Main Article Content

Aleksandra Szczawinska-Poplonyk
Kinga Begier
Alicja Dorota
Monika Dabrowska
Dominika Galecka
Kamila Wawrzeniak
Kamil Wroblewski


primary immunodeficiency, infection, autoimmunity, malignancy, children, syndromes


Background: Syndromic immunodeficiencies are a genetically and pathophysiologically heterogeneous group of inborn errors of immunity. These are characterized by multiple extra immune clinical symptoms and a wide range of immunological phenotypes with increased susceptibility to infections, autoimmune phenomena, immune dysregulation, organ-specific
pathology, and malignancy.
Objective: To increase the pediatricians’ awareness of this multifaceted group of primary immunodeficiencies in children.
Methods: A comprehensive review of genetic background and clinical symptomatology of syndromic immunodeficiencies as well as current diagnostic approach and treatment modalities.
Results: From the pediatrician’s perspective, an early-life diagnosis of syndromic immunodeficiencies, which is frequently indispensable for successful life-saving immunocorrection, poses a diagnostic challenge. Increased pediatricians’ awareness to recognize signs and symptoms of these diseases in affected children is of paramount importance. Current advances in molecular  biotechnology and immunogenetics, resulting in the implementation of newborn screening and new-generation sequencing, provide informative tools for definitive diagnosis and, in many new disease entities, for their definition and genotype–phenotype delineation and correlation.
Conclusions: A broad spectrum of clinical phenotypes in children with syndromic primary immunodeficiencies requires pediatrician’s special attention, that is, individualized multidisciplinary approach under the supervision of a clinical immunologist.

Abstract 104 | PDF Downloads 72 XML Downloads 6 HTML Downloads 1


1. de Vries E, Driessen G. Educational paper: Pprimary immunodeficiencies in children: a diagnostic challenge. Eur J Pediatr 2011;170:169-–177.
2. Kersseboom R, Brooks A, Weemaes C. Educational paper: Syndromic forms of primary immunodeficiency. Eur J Pediatr 2011;170:295-–308.
3. Schatorje E, van der Flier M, Seppanen M, Browning M, Morsheimer M, Henriet S, et al. Primary immunodeficiency associated with chromosomal aberration - —aAn ESID survey. Orphanet J Rare Dis 2016;11:110.
4. Conde CD, Petronczki OY, Baris S, Willmann KL, Girardi E, Salzer E, et al. Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress. J Clin Invest 2019;129:4194-–4206.

5. Meyts I, Aksentijevich I. Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the phenotype, genetics, pathogenesis, and treatment. J Clin Immunol 2018;38:569-–578.
6. Szczawińska-Popłonyk A, Płoski R, Bernatowska E, Pac M. A novel CDC42 mutation in an 11-year old child manifesting as syndromic immunodeficiency, autoinflammation, hemophagocytic lymphohistiocytosis, and malignancy: a case report. Front Immunol 2020;11:318.
7. Martinelli S, Krumbach OHF, Pantaleoni F, Coppola S, Amin E, Pannone I, et al. Functional dysregulation in CDC42 cause diverse clinical phenotypes. Am J Hum Genet 2018;102:309-–320.
8. Lam MT, Coppola S, Krumbach OHF, Prencipe G, Insalaco A, Cifaldi C, et al. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. J Exp mMed 2019;216:2778-–2799.
9. Motokawa M, Watanabe S, Nakatomi A, Kondoh T, Matsumoto T, Morifuji K, et al. A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-–Kosaki syndrome. J Hum Genet 2018;63:387-–390.
10. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2020;40:24-–64.
11. Ram G, Chinen J. Infections and immunodeficiency in Down syndrome. Clin Exp Immunol 2011;164:9-–16.
12. Kusters MAA, Verstegen RHJ, Gemen EFA. Intrinsic defects of the immune system in children with Down syndrome: aA review. Clin Exp Immunol 2009;156:189-–193.
13. Satge D, Seidel MG. The pattern of malignancies in Down syndrome and its potential context with the immune system. Front Immunol 2018;9:3058.
14. Zampieri BL, Biselli-Perico JM, Santana de Souza JE, Carvalho Burger M, Araujo Silva W, Goloni-Bertollo EM, et al. Altered expression of immune-related genes in children with Down syndrome. PLoS One 2014;9:107218.
15. Verstegen RHJ, Kusters MAA, Gemen EFA, de Vries E. Down syndrome lymphocyte subpopulations, intrinsic defect or decreased T-lymphocyte help. Ped Res. 2010;67:563-–569.
16. Verstegen RHJ, Driessen GJ, Bartol SJW, van Noessel CJM, Boon L, van der Burg M, et al. Defective B-cell memory in patients with Down syndrome. J Allergy Clin Immunol 2014;134:1346-–1353.
17. Mitwalli M, Wahba Y, Shaltout A, Gouida M. Lymphocyte subgroups and recurrent infections in children with Down syndrome - —aA prospective case control study. Centr Eur J Immunol 2018;43:258-–254.
18. Huggard D, Doherty DG, Molloy EJ. Immune dysregulation in children with Down syndrome. Front Pediatr 2020;8:73.
19. Fraga Mattos MF, Matos Biselli-Chicote P, Matos Biselli J, da Silva Asembleia TL, Goloni-Bertollo EM, Pavarino EC. Interleukin 6 and 10 serum levels and genetic polymorphisms in children with Down syndrome. Mediators Inflamm 2018;2018:6539548.
20. McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JAS, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers 2016;1:15071.
21. Du Q, de la Morena MT, van Oers NCS. The genetics and epigenetics of 22q11.2 deletion syndrome. Front Genet 2020;10:1365.
22. Morrow B, McDonald-McGinn DM, Emanuel BS, Vermeesch JR, Scambler PJ. Molecular genetics of 22q11.2 deletion syndrome. Am J Med Genet A. 2018;176:2070-–2081.
23. Komasińska P, Szczawińska-Popłonyk A, Jończyk-Potoczna K, Bręborowicz A. Congenital atresia of the larynx and esophagus in a girl with 22q.11.2 deletion - —cCase report. Pol J Pediatr 2017;92:335-–341.
24. Sullivan KE, Crowley B, Maurer K, Goldmuntz E, Gaynor JW, Zackai E, et al. T-cell lymphopenia in 22q11.2 deletion syndrome: Relationship to cardiac disease. J Allergy Clin Immunol Pract 2018;6:690-–691.
25. Marcovecchio GE, Bortolomai I, Ferrua F, Fontana E, Imberti L, Conforti E, et al. Thymic epithelium abnormalities in DiGeorge and Down syndrome patients contribute to dysregulation in T cell development. Front Immunol 2019;10:447.
26. Cohen JL, Crowley TB, McGinn DE, McDougall C, Unolt M, Lambert MP, et al. 22q and two: 22q11.2 deletion syndrome and coexisting conditions. Am J Med Genet 2018;176:2203-–2214.
27. Crowley B, Ruffner M, McDonald-McGinn DM, Sullivan KE. Variable immune deficiency related to deletion size in chromosome 22q11.2 deletion syndrome. Am J Med Genet A 2018;176:2082-–2086.
28. Klocperk A, Parackova Z, Bloomfield M, Rataj M, Pokorny J, Unger S, et al. Follicular helper T cells in DiGeorge syndrome. Front Immunol 2018;9:1730.
29. Gennery AR. Immunological features of 22q11 deletion syndrome. Curr Opin Pediatr 2013;25:730-–735.
30. Kuo CY, Signer R, Saitta SC. Immune and genetic features of the chromosome 22q11.2 deletion (DiGeorge) syndrome. Curr Allergy Asthma Rep 2018;18:75.
31. Davies GE, Cheung M , Gilmour K, Maimaris J, Curry J, Furmanski A, et al. Thymus transplantation for complete DiGeorge syndrome: European experience. J Allergy Clin Immunol 2017;140:1660-–1670.
32. Janssen N, Bergman JE, Swertz MA, Tranebjaerg L, Lodahl M, Schoots J, et al. Mutation update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat. 2012;33:1149-–1160.
33. Bergman JE, Janssen N, Hoefsloot LH, Jongmans MC, van Ravenswaaij-Arts CM. CHD7 mutations and CHARGE syndrome: tThe clinical implications of an expanding phenotype. J Med Genet 2011;48:334-–342.
34. Hale CL, Niederriter AN, Green GE, Martin DM. Atypical phenotypes associated with pathogenic CHD7 variants and a proposal for broadening CHARGE syndrome clinical diagnostic criteria. Am J Med Genet A 2016;170A:344-–354.
35. Liu ZZ, Wang ZL, Choi TI, Huang WT, Wang HT, Han YY, et al. Chd7 is critical for early T-cell development and thymus organogenesis in zebrafish. Am J Pathol 2018;188:1043-–1058.
36. Wong MTY, Scholvinck EH, Lambeck AJA, Ravenswaaij-Arts CMA. CHARGE syndrome: aA review of the immunological aspects. Eur J Hum Genet 2015;23:1451-–1459.
37. Wong MTY, Lambeck AJA, van der Burg M, la Bastide-van Gemert S, Hogendorf LA, van Ravenswaaij-Arts CMA, et al. Immune dysfunction in children with CHARGE syndrome: aA cross-sectional study. PLoS One 2015;10:e0142350.
38. Mehr S, Hsu P, Campbell D. Immunodeficiency in CHARGE syndrome. Am J Med Genet Semin Med Genet 2017;175:516-–523.
39. Jyonouchi S, McDonald-McGinn DM, Bale S, Zackai EH, Sullivan KE. CHARGE syndrome and chromosome 22q11.2 deletion syndrome: aA comparison of immunologic and nonimmunologic phenotypic features. Pediatrics 2009;123:e871-–e877.
40. Kong F, Martin DM. Atopic disorders in CHARGE syndrome: aA retrospective study and literature review. Eur J Med Genet 2018;61:225-–229.
41. Hsu P, Ma A, Barnes EH, Wilson M, Hoefsloot LH, Rinne T, Munns C, et al. The immune phenotype of patients with CHARGE syndrome. J Allergy Clin Immunol Pract 2016;4:96-–103.
42. McKinnon PJ. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol Mech Dis. 2012;7:303-–321.
43. Ambrose M, Gatti RA. Pathogenesis of ataxia-telangiectasia: tThe next generation of ATM functions. Blood 2013;121:4036-–4045.
44. Zaki-Dizaji M, Akrami SM, Abolhassani H, Rezaei N, Aghamohammadi A. Ataxia telangiectasia syndrome: mMoonlighting ATM. Expert Rev Clin Immunol. 2017;13:1155-–1172.
45. Zaki-Dizaji M, Akrami M, Azizi G, Abolhassani H, Aghamohammadi A. Inflammation, a significant player of ataxia-telangiectasia pathogenesis? Inflamm Res. 2018:67:559-–570.
46. Taylor AMR, Lam Z, Last JI, Byrd PJ. Ataxia telangiectasia: mMore variation at clinical and cellular levels. Clin Genet 2015;87:199-–208.
47. Amirifar P, Ranjouri MR, Yazdani R, Abolhassani H, Aghamohammadi A. Ataxia-telangiectasia: aA review of clinical features and molecular pathology. Pediatr Allergy Immunol 2019;30:277-–288.
48. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia-telangiectasia: aA review. Orphanet J Rare Dis 2016;11:159.
49. Bhatt JM, Bush A, van Gerven M, Nissenkorn A, Renke M, Yarlett L, et al. ERS statement on the multidisciplinary respiratory management of ataxia telangiectasia. Eur Respir J 2015;46:1557-–1560.
50. Boohaker RJ, Xu B. The versatile functions of ATM kinase. Biomed J. 2014;37:3-–9.
51. Driessen GJ, Ijspeert H, Weemaes CMR, Haraldsson A, Trip M, Warris A, et al. Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. J Allergy Clin Immunol 2013;131:1367-–1375.
52. Kraus M, Lev A, Simon AJ, Levran I, Nissenkorn A, Levi YB, et al. Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia. J Clin Immunol 2014;34:561-–572.
53. Amirifar P, Mozdarani H, Yazdani R, Kiaei F, Moeini Shad T, Shahkarami S, et al. Effect of class switch recombination defect on the phenotype of ataxia-telangiectasia patients. Immunol Invest 2020;2:1-–15.
54. Krauthammer A, Lahad A, Goldberg L, Sarouk I, Weiss B, Somech R, et al. Elevated IgM levels as a marker for a unique phenotype in patients with ataxia telangiectasia. BMC Pediatr 2018;18:185.
55. Meyer AK, Banks M, Nadasdy T, Clark JJ, Zheng R, Gelfand EW, et al. Vasculitis in a child with the hyper-IgM variant of ataxia-telangiectasia. Front Pediatr 2019;7:390.
56. Souarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d'Enghien C, Brousse N, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: aA report from French national registry of primary immune deficiencies. J Clin Oncol 2015;33:202-–208.
57. Vukic M, Daxinger L. DNA methylation in disease: iImmunodeficiency, centromeric instability, facial anomalies syndrome. Essays Biochem 2019;63:773-–783.
58. Staines Boone AT, Chinn IK, Alaez-Verson C, Yamazaki-Nakashimada MA, Carrillo-Sanchez K, Garcia-Cruz MH, et al. Failing to make ends meet: tThe broad clinical spectrum of DNA Ligase IV deficiency. Case series and review of the literature. Front Pediatr 2019;6:426.
59. Volk T, Pannicke U, Reisli I, Bulashevska A, Ritter J, Bjorkman A, et al. DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Hum Mol Genet 2015;24:7361-–7372.
60. Cipe FE, Aydogmus C, Babayigit Hocaoglu A, Kilic M, Kaya GD, Gulec EY. Cernunnos/XLF deficiency: aA syndromic primary immunodeficiency. Case Rep Pediatr 2014;2014:614238.
61. Lobachevsky P, Woodbine L, Hsiao K, Choo S, Fraser Ch, Gray P, et al. Evaluation of severe combined immunodeficiency pediatric patients on the basis of cellular radiosensitivity. J Mol Diagn 2015:17:560-–575.
62. Varon R, Seemanova E, Chrzanowska K, Hnateyko O, Piekutowska-Abramczuk D, Krajewska-Walasek M, et al. Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet 2000;8:900-–902.
63. Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis 2012;7:13
64. Wolska-Kuśnierz B, Gregorek H, Chrzanowska K, Piątosa B, Pietrucha B, Heropolitańska-Pliszka E. Nijmegen breakage syndrome: Clinical and immunological features, long-term outcome and treatment options - —aA retrospective analysis. J Clin Immunol 2015;35:538-–549.
65. Marczak H, Heropolitańska-Pliszka E, Langfort R, Roik D, Grzela K. Nijmegen breakage syndrome complicated with primary pulmonary granulomatosis. Pediatrics 2018;142:e20180122.
66 . Renzi S, Langenberg-Ververgaert KPS, Waespe N, Ali S, Bartram J, Michaeli O, et al. Primary immunodeficiencies and their associated risk of malignancies in children: an overview. Eur J Pediatr 2020; doi: 10.1007/s00431-020-03619-2.
67. Wolska-Kuśnierz B, Gennery A. Hematopoietic stem cell transplantation for DNA double strand breakage repair disorders. Front Pediatr 2020;7:557.
68. Piątosa B, van der Burg M, Siewiera K, Pac M, van Dongen JJM, Langerak AW, et al. The defect in humoral immunity in patients with Nijmegen breakage syndrome is explained by defects in peripheral B lymphocyte maturation. Cytometry A 2012;81A:835-–842.
69. Meijers RWJ, Dzierżanowska-Fangrat K, Zborowska M, Solarska I, Tielemans D, van Turnhout BAC, et al. Circulating T cells of patients with Nijmegen breakage syndrome show signs of senescence. J Clin Immunol 2017;37:133-–142.
70. Bergerson JRE, Freeman AF. An update on syndromes with a hyper-IgE phenotype. Immunol Allergy Clin N Am 2019;39:49-–61.
71. Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ, et al. Germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 2017;49:1192-–1201.
72. Beziat V, Li J, Lin JX, Ma CS, Li P, Bousfisha A, et al. A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity. Sci Immunol 2018;3:pii:eaat4956.
73. Lyons JJ, Liu Y, Ma CA, Yu X, O'Connell MP, Lawrence MG, et al. ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans. Exp Med 2017;214:669-–680.
74. Beziat V, Tavernier SJ, Chen YH, Ma CS, Materna M, Laurence A, et al. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. J Exp Med. 2010;217:pii:e20191804.
75. Shahin T, Aschenbrenner D, Cagdas D, Kostel Bal S, Dominguez Conte C, Garncarz W, et al. Selective loss of function variants in IL6ST cause hyper-IgE syndrome with distinct impairments of T-cell phenotype and function. Haematologica 2019;104:609-–621.
76 . Zhang Q, Boisson B, Beziat V, Puel A, Casanova J. Human hyper-IgE syndrome: sSingular or plural? Mamm Genome 2018;29:603-–617.
77. Yong PFK, Freeman AF, Engelhardt KR, Holland S, Puck JM, Grimbacher B. An update on the hyper-IgE syndromes. Arthritis Res Ther 2012;14:228.
78. Al-Shaikhly T, Ochs HD. Hyper-IgE syndromes: cClinical and molecular characteristics. Immunol Cell Biol 2019;97:368-–379.
79. Schimke LF, Sawalle-Belohradsky J, Roesler J, et al. Diagnostic approach to the hyper-IgE syndromes: iImmunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis. J Allergy Clin Immunol 2010;126:611-–617.
80. Hagl B, Heinz V, Schlesinger A, et al. Key findings to expedite the diagnosis of hyper-IgE syndromes in infants and young children. Pediatr Allergy Immunol. 2016;27:177-–184.
81. Szczawińska-Popłonyk A, Kycler Z, Pietrucha B, Heropolitańska-Pliszka E, Bręborowicz A, Gerreth K. The hyperimmunoglobulin E syndrome - —cClinical manifestation diversity in primary immunodeficiency. Orphanet J Rare Dis 2011;6:76.
82. Freeman AF, Olivier KN. Hyper IgE syndromes and the lung. Clin Chest Med 2016;37:557-–567.
83. Liu JY, Li Q, Chen TT, Guo X, Ge J, Yuan LX. Destructive pulmonary staphylococcal infection in a boy with hyper-IgE syndrome: aA novel mutation in the signal transducer and activator of transcription (STAT3) gene (p.Y657S). Eur J Pediatr 2011;170:661-–666.
84. Chandesris M, Melki I, Natividad A, Puel A, Fieschi C, Yun L, et al. Autosomal dominant STAT3 deficiency and hyper-IgE syndrome molecular, cellular, and clinical features from a French National Survey. Medicine (Baltimore) 2012;91:e1-–19.
85. Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, et al. Deficiency in Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med. 2008;205:1551-–1557.
86. Sharma S, Saikia B, Goel S, Rawat A, Minz RW, Suri D, et al. TH17 cells in STAT3 related hyper-IgE syndrome. Indian J Pediatr 2016;83:1104-–1108.
87. Van de Veen W, Kratz CE, McKenzie CI, et al. Impaired memory B-cell development and antibody maturation with a skewing toward IgE in patients with STAT3 hyper-IgE syndrome. Allergy 2019;74:2394-–2405.
88. Su HC, Jing H, Angelus P, Freeman AF. Insight into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunol Rev 2019;287:9-–19.
89. Yang L, Fliegauf M, Grimbacher B. Hyper-IgE syndromes: rReviewing PGM3 deficiency. Curr Opin Pediatr 2014;26:697-–703.
90. El-Sayed ZA, Radwan N. Newborn screening for primary immunodeficiencies: tThe gaps, challenges, and outlook for developing countries. Front Immunol 2020;10:2987.
91. Jiang T, Li Z, Zhang Q. Advances in neonatal screening for primary immune deficiencies. Exp Ther Med 2016;11:1542-–1544.
92. Mandola AB, Reid B, Sirror R, Dent P, Chakroborty P, Bulman DE, et al. Ataxia telangiectasia diagnosed on newborn screening - —cCase cohort of 5 years' experience. Front Immunol 2019;10:2940.
93. Amatuni GS, Currier RJ, Church JA, Bishop T, Grimbacher E, Anh-Chuong Nguyen A, et al. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California, 2010-–2017. Pediatrics 2019;143:e20182300.
94. Puck JM. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia. Immunol Rev 2019;287:241-–252.
95. Kwan A, Roshini AS, Currier R, Brower A, Andruszewski K, Abbott JK, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA 2014;312:729-–738.
96. Korsunskiy I, Blyuss O, Gordukova M, Davydova N, Zaikin A, Zinovieva N, et al. Expanding TREC and KREC utility in primary immunodeficiency diseases diagnosis. Front Immunol 2020;11:320.
97. Korsunskiy I, Blyuss O, Gordukova M, Davydova N, Gordleeva S, Molchanov R, et al. TREC and KREC levels as predictors of lymphocyte subpopulations measured by flow cytometry. Front Physiol 2019;9:1877.
98. Acosta S, Torres V, Paulos M, Cifuentes I. CLOVES syndrome: sSevere neonatal presentation. J Clin Diagn Res 2017;11:TR01-–TR03.
99. Punwani D, Zhang Y, Yu J, Cowan MJ, Rana S, Kwan A, et al. Multisystem anomalies in severe combined immunodeficiency with mutant BCL11B. N Engl J Med. 2016;375:2165-–2176.
100. Volpi S, Yamazaki Y, Brauer PM, van Rooijen E, Hayashida A, Slavotinek A, et al. EXTL mutations cause skeletal dysplasia, immune deficiency, and developmental delay. Exp Med 2017;214:623-–637.
101. Jyonouchi S, Jongco AM, Puck J, Sullivan KE. Immunodeficiencies associated with abnormal newborn screening for T cell and B cell lymphopenia. J Clin Immunol 2017;37:363-–374.
102. Knight V. The utility of flow cytometry for the diagnosis of primary immunodeficiencies. Int J Lab Hematol 2019;41:63-–72.
103. Rawat A, Arora K, Shandilya J, Vignesh P, Suri D, Kaur G, et al. Flow cytometry for diagnosis of primary immunodeficiencies - —aA tertiary center experience from North India. Front Immunol 2019;10:2111.
104. Van der Burg M, Kalina T, Perez-Andres M, Vlkova M, Lopez-Granados E, Blanco E, et al. The EuroFlow orientation tube for cytometric diagnostic screening of primary immunodeficiencies of the lymphoid system. Front Immunol 2019;10:246.
105. Kalina T, Bakardijeva M, Blom M, Perez-Andres M, Barenregt B, Kanderova V, et al. EuroFlow standardized approach to diagnostic immunophenotyping of severe PID in newborns and young children. Front Immunol 2020;11:371.
106. De Vries E, in collaboration with European Society for Immunodeficiencies (ESID) members. Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol 2012;167:108-–119.
107. Seleman M, Hoyos-Bachiloglu R, Geha R, Chou J. Uses of next-generation sequencing technologies for the diagnosis of primary immunodeficiencies. Front Immunol 2017;8:847.
108. Rudilla F, Franco-Jarava C, Martinez-Gallo M, Garcia-Prat M, Martin-Nalda A, Riviere J, et al. Expanding the clinical and genetic spectra of primary immunodeficiency-related disorders with clinical exome sequencing: eExpected and unexpected findings. Front Immunol 2019;10:2325.
109. Rae W, Ward D, Mattocks C, Pengelly RJ, Eren E, Patel SV. Clinical efficacy of a next-generation sequencing gene panel for primary immunodeficiency diagnostics. Clin Genet 2018;93:647-–655.
110. Bucciol G, van Nieuwenhove E, Moens L, Itan Y, Meyts I. Whole exome sequencing in inborn errors of immunity: uUse the power but mind the limits. Curr Opin Allergy Clin Immunol 2017;17:421-–430.
111. Bucciol G, Meyts I. Recent advances in primary immunodeficiency: fFrom molecular diagnosis to treatment. F1000Res 2020; 9:194.
112. Poyhonen L, Bustamante J, Casanova JL, Jouanguy E, Zhang Q. Life-threatening infections due to live-attenuated vaccines: eEarly manifestations of inborn errors of immunity. J Clin Immunol 2019;39:376-–390.
113. Nunes-Santos CJ, Rosenzweig SD. Bacille Calmette-–Guerin complications in newly described primary immunodeficiency diseases: 2010-–2015. Front Immunol 2018;9:1423.
114. Bernatowska E, Skomska-Pawliszak M, Wolska-Kuśnierz B, Pac M, Heropolitańska-Pliszka E, Pietrucha B, et al. BCG Moreau vaccine safety profile and NK cells - —dDouble protection against disseminated BCG infection in retrospective study of vaccination in 52 Polish children with severe combined immunodeficiency. J Clin Immunol 2020;40:138-–146.
115. Shearer WT, Fleisher TA, Buckley RH, Ballas Z, Ballow M, Blaese M, et al. Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol 2014;133:961-–966.
116. Gernez Y, Baker MG, Maglione PJ. Humoral immunodeficiencies: cConferred risk of infections and benefits of immunoglobulin replacement therapy. Transfusion 2018;58:3056-–3064.
117. Jolles S, Chapel H, Litzman J. When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: aA practical approach. Clin Exp Immunol 2016;188:333-–341.
118. Bienvenu B, Cozon G, Hoarau C, Pasquet M, Cherin P, Clerson P, et al. Does the route of administration of immunoglobulin replacement therapy impact quality of life and satisfaction in patients with primary immunodeficiency? Insights from the French cohort "Visages". Orphanet J Rare Dis 2016;11:83.
119. Shresthra P, Karmacharya P, Wang Z, Donato A, Joshi AY. Impact of IVIg vs. SCIg on IgG through level and infection incidence in primary immunodeficiency diseases: aA systematic review and meta-analysis of clinical studies. World Allergy Org J 2019;12:100068.
120. Kuruvilla M, de la Morena MT. Antibiotic prophylaxis in primary immune deficiency disorders. J Allergy Clin Immunol 2013; 1:573-–582.
121. Pizzutto SJ, Hare KM, Upham JW. Bronchiectasis in children: cCurrent concepts in immunology and microbiology. Front Pediatr 2017;5:123.
122. Sobh A, Bonilla FA. Vaccination in primary immunodeficiency. J Allergy Clin Immunol Pract 2016;4:1066-–1075.
123. Bonilla FA. Update: Vaccines in primary immunodeficiency. J Allergy Clin Immunol 2018;141:474-–481.
124. Papadoupoulou-Alataki E, Hassan A, Davies G. Prevention of infection in children and adolescents with primary immunodeficiency disorders. Asian Pac J Allergy Immunol 2012;30:249-–258.
125. Altmann T, Gennery AR. DNA Ligase IV syndrome; a review. Orphanet J Rare Dis 2026;11:137.
126. Sassi A, Lazaroski S, Wu G, Haslam SM, Fliegauf M, Mellouli F, et al. Hypomorphic, homozygous mutations in Phosphoglucomutase 3 impair immunity and increase serum levels. J Allergy Clin Immunol 2014;133:1410-–1419.
127. Castagnoli R, Delmonte OM, Calzoni E, Notarangelo LD. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: cCurrent status and future perspectives. Front Pediatr 2019;7:295.
128. Delmonte OM, Notarangelo LD. Targeted therapy with biologicals and small molecules in primary immunodeficiencies. Med Princ Pract 2020;29:101-–112.
129. Leiding JW, Forbes LR. Mechanism-based precision therapy for the treatment of primary immunodeficiency and primary immunodysregulatory diseases. J Allergy Clin Immunol Pract 2019;7:761-–773.
130. Booth C, Romano R, Roncarolo MG, Thrasher AJ. Gene therapy for primary immunodeficiency. Hum Mol Genet 2019;28:15-–23.
131. Zhang Z, Thrasher AJ, Zhang F. Gene therapy and genome editing for primary immunodeficiency diseases. Genes Dis 2019;7:38-–51.