Skip to main content

ICON: The Early Diagnosis of Congenital Immunodeficiencies

Journal of Clinical Immunology volume 34, pages 398–424 (2014)Cite this article

Abstract

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

Abbreviations

AD-EDA-ID:

Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency

AD-HIES:

Autosomal dominant hyper IgE syndrome

AR-HIES:

Autosomal recessive hyper IgE syndrome

AT:

Ataxia telangiectasia

ATM:

Ataxia-telangiectasia mutated

BCG:

Bacillus Calmette-Guérin

CGD:

Chronic granulomatous disease

CID:

Combined immunodeficiencies

CMC:

Chronic Mucocutaneous Candidiasis

CSR:

Class switch recombination

DHR:

Dihydrorhodamine–1,2,3

EDA:

Anhidrotic ectodermal dysplasia

G-CSF:

Granulocyte colony-stimulating factor

GVHD:

Graft-versus-host disease

HSCT:

Hematopoietic stem-cell transplantation

HSE:

Herpes simplex encephalitis

HSV1:

Herpes simplex virus type 1

ICON:

International consensus

IVIG:

Intravenous immunoglobulin

LAD-I:

Leukocyte adhesion deficiency type I

LAD-II:

Leukocyte adhesion deficiency type II

LAD-III:

Leukocyte adhesion deficiency type III

MSMD:

Mendelian susceptibility to mycobacterial diseases

NBS:

Newborn screening

NBT:

Nitroblue tetrazolium

OSM:

Oncostatin M

PID:

Primary immunodeficiency

SCID:

Severe combined immunodeficiency

SHM:

Somatic hyper mutation

STAT3:

Signal transducer and activator of transcription 3

TIR:

Toll-IL-1R

TLR:

Toll-like receptors

TREC:

T cell receptor excision circle

WAS:

Wiskott-Aldrich syndrome

WASp:

Wiskott-Aldrich syndrome protein

XHIGM:

X-linked hyper IgM

XLA:

X-linked agammaglobulinemia

XLT:

X-linked thrombocytopenia

XR-EDA-ID:

X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency

References

  1. Chou J, Hanna-Wakim R, Tirosh I, Kane J, Fraulino D, Lee YN, et al. A novel homozygous mutation in recombination activating gene 2 in 2 relatives with different clinical phenotypes: Omenn syndrome and hyper-IgM syndrome. J Allergy Clin Immunol. 2012;130(6):1414–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Keller MD, Ganesh J, Heltzer M, Paessler M, Bergqvist AG, Baluarte HJ, et al. Severe combined immunodeficiency resulting from mutations in MTHFD1. Pediatrics. 2013;131(2):629–34.

    Google Scholar 

  3. Maggina P, Gennery AR. Classification of primary immunodeficiencies: need for a revised approach? J Allergy Clin Immunol. 2012;131(2):292–4.

    Google Scholar 

  4. Kawai T, Akira S. Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci. 2008;1143:1–20.

    CAS  PubMed  Google Scholar 

  5. O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7(5):353–64.

    PubMed  Google Scholar 

  6. Picard C, Casanova JL, Puel A. Infectious diseases in patients with IRAK-4, MyD88, NEMO, or IkappaBalpha deficiency. Clin Microbiol Rev. 2011;24(3):490–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Sancho-Shimizu V, Perez de Diego R, Lorenzo L, Halwani R, Alangari A, Israelsson E, et al. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J Clin Invest. 2011;121(12):4889–902.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Herman M, Ciancanelli M, Ou YH, Lorenzo L, Klaudel-Dreszler M, Pauwels E, et al. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood. J Exp Med. 2012;209(9):1567–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-kappaB-mediated immunity in man. Curr Opin Immunol. 2004;16(1):34–41.

    CAS  PubMed  Google Scholar 

  10. Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–7.

    CAS  PubMed  Google Scholar 

  11. Casrouge A, Zhang SY, Eidenschenk C, Jouanguy E, Puel A, Yang K, et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science. 2006;314(5797):308–12.

    CAS  PubMed  Google Scholar 

  12. Perez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S, Picard C, et al. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity. 2010;33(3):400–11.

    CAS  PubMed  Google Scholar 

  13. Sancho-Shimizu V, Perez de Diego R, Jouanguy E, Zhang SY, Casanova JL. Inborn errors of anti-viral interferon immunity in humans. Curr Opin Virol. 2011;1(6):487–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science. 2003;299(5615):2076–9.

    CAS  PubMed  Google Scholar 

  15. von Bernuth H, Picard C, Puel A, Casanova JL. Experimental and natural infections in MyD88- and IRAK-4-deficient mice and humans. Eur J Immunol. 2012;42(12):3126–35.

    Google Scholar 

  16. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321(5889):691–6.

    Google Scholar 

  17. Conway DH, Dara J, Bagashev A, Sullivan KE. Myeloid differentiation primary response gene 88 (MyD88) deficiency in a large kindred. J Allergy Clin Immunol. 2010;126(1):172–5.

    CAS  PubMed  Google Scholar 

  18. Picard C, von Bernuth H, Ghandil P, Chrabieh M, Levy O, Arkwright PD, et al. Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine (Baltimore). 2010;89(6):403–25.

    CAS  Google Scholar 

  19. Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000;67(6):1555–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001;27(3):277–85.

    CAS  PubMed  Google Scholar 

  21. Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ, et al. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol. 2008;122(6):1169 e16–77 e16.

    Google Scholar 

  22. Hubeau M, Ngadjeua F, Puel A, Israel L, Feinberg J, Chrabieh M, et al. New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein. Blood. 2011;118(4):926–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Kawai T, Nishikomori R, Izawa K, Murata Y, Tanaka N, Sakai H, et al. Frequent somatic mosaicism of NEMO in T cells of patients with X-linked anhidrotic ectodermal dysplasia with immunodeficiency. Blood. 2012;119(23):5458–66.

    CAS  PubMed  Google Scholar 

  24. Kawai T, Nishikomori R, Heike T. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergol Int. 2012;61(2):207–17.

    CAS  PubMed  Google Scholar 

  25. Mooster JL, Cancrini C, Simonetti A, Rossi P, Di Matteo G, Romiti ML, et al. Immune deficiency caused by impaired expression of nuclear factor-kappaB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of the NEMO gene. J Allergy Clin Immunol. 2010;126(1):127 e7–32 e7.

    Google Scholar 

  26. Courtois G, Smahi A, Reichenbach J, Döffinger R, Cancrini C, Bonnet M, et al. A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T-cell immunodeficiency. J Clin Invest. 2003;112(7):1108–15.

    Google Scholar 

  27. Janssen R, van Wengen A, Hoeve MA, ten Dam M, van der Burg M, van Dongen J, et al. The same IkappaBalpha mutation in two related individuals leads to completely different clinical syndromes. J Exp Med. 2004;200(5):559–68.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. McDonald DR, Mooster JL, Reddy M, Bawle E, Secord E, Geha RS. Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency. J Allergy Clin Immunol. 2007;120(4):900–7.

    CAS  PubMed  Google Scholar 

  29. Lopez-Granados E, Keenan JE, Kinney MC, Leo H, Jain N, Ma CA, et al. A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum Mutat. 2008;29(6):861–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Ohnishi H, Miyata R, Suzuki T, Nose T, Kubota K, Kato Z, et al. A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome. J Allergy Clin Immunol. 2012;129(2):578–80.

    PubMed  Google Scholar 

  31. Schimke LF, Rieber N, Rylaarsdam S, Cabral-Marques O, Hubbard N, Puel A, et al. A novel gain-of-function IKBA mutation underlies ectodermal dysplasia with immunodeficiency and polyendocrinopathy. J Clin Immunol. 2013;33(6):1088–99.

    CAS  PubMed  Google Scholar 

  32. Dupuis-Girod S, Cancrini C, Le Deist F, Palma P, Bodemer C, Puel A, et al. Successful allogeneic hemopoietic stem cell transplantation in a child who had anhidrotic ectodermal dysplasia with immunodeficiency. Pediatrics. 2006;118(1):e205–11.

    PubMed  Google Scholar 

  33. Fish JD, Duerst RE, Gelfand EW, Orange JS, Bunin N. Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency. Bone Marrow Transplant. 2009;43(3):217–21.

    CAS  PubMed  Google Scholar 

  34. Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, Rizzi M, et al. Deficiency of innate and acquired immunity caused by an IKBKB mutation. N Engl J Med. 2013;369(26):2504–14.

    CAS  PubMed  Google Scholar 

  35. Winkelstein JA, Marino MC, Johnston Jr RB, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000;79(3):155–69.

    CAS  Google Scholar 

  36. Johnston Jr RB. Clinical aspects of chronic granulomatous disease. Curr Opin Hematol. 2001;8(1):17–22.

    PubMed  Google Scholar 

  37. Holland SM. Chronic granulomatous disease. Clin Rev Allergy Immunol. 2010;38(1):3–10.

    CAS  PubMed  Google Scholar 

  38. de Oliveira-Junior EB, Bustamante J, Newburger PE, Condino-Neto A. The human NADPH oxidase: primary and secondary defects impairing the respiratory burst function and the microbicidal ability of phagocytes. Scand J Immunol. 2011;73(5):420–7.

    PubMed  Google Scholar 

  39. Marciano BE, Rosenzweig SD, Kleiner DE, Anderson VL, Darnell DN, Anaya-O’Brien S, et al. Gastrointestinal involvement in chronic granulomatous disease. Pediatrics. 2004;114(2):462–8.

    PubMed  Google Scholar 

  40. Dinauer MC, Orkin SH, Brown R, Jesaitis AJ, Parkos CA. The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature. 1987;327(6124):717–20.

    CAS  PubMed  Google Scholar 

  41. Clark RA, Malech HL, Gallin JI, Nunoi H, Volpp BD, Pearson DW, et al. Genetic variants of chronic granulomatous disease: prevalence of deficiencies of two cytosolic components of the NADPH oxidase system. N Engl J Med. 1989;321(10):647–52.

    CAS  PubMed  Google Scholar 

  42. Dinauer MC, Pierce EA, Bruns GA, Curnutte JT, Orkin SH. Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease. J Clin Invest. 1990;86(5):1729–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Parkos CA, Dinauer MC, Walker LE, Allen RA, Jesaitis AJ, Orkin SH. Primary structure and unique expression of the 22-kilodalton light chain of human neutrophil cytochrome b. Proc Natl Acad Sci U S A. 1988;85(10):3319–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Matute JD, Arias AA, Wright NA, Wrobel I, Waterhouse CC, Li XJ, et al. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40 phox and selective defects in neutrophil NADPH oxidase activity. Blood. 2009;114(15):3309–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Accetta D, Syverson G, Bonacci B, Reddy S, Bengtson C, Surfus J, et al. Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J Allergy Clin Immunol. 2011;127(2):535–8 e1-2.

    Google Scholar 

  46. Ambruso DR, Knall C, Abell AN, Panepinto J, Kurkchubasche A, Thurman G, et al. Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A. 2000;97(9):4654–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Rae J, Newburger PE, Dinauer MC, Noack D, Hopkins PJ, Kuruto R, et al. X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase. Am J Hum Genet. 1998;62(6):1320–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Roos D. X-CGDbase: a database of X-CGD-causing mutations. Immunol Today. 1996;17(11):517–21.

    CAS  PubMed  Google Scholar 

  49. Roos D, de Boer M, Kuribayashi F, Meischl C, Weening RS, Segal AW, et al. Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease. Blood. 1996;87(5):1663–81.

    CAS  PubMed  Google Scholar 

  50. Roos D, Kuhns DB, Maddalena A, Roesler J, Lopez JA, Ariga T, et al. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells Mol Dis. 2010;45(3):246–65.

    CAS  PubMed  Google Scholar 

  51. Agudelo-Florez P, Prando-Andrade CC, Lopez JA, Costa-Carvalho BT, Quezada A, Espinosa FJ, et al. Chronic granulomatous disease in Latin American patients: clinical spectrum and molecular genetics. Pediatr Blood Cancer. 2006;46(2):243–52.

    PubMed  Google Scholar 

  52. Kuhns DB, Alvord WG, Heller T, Feld JJ, Pike KM, Marciano BE, et al. Residual NADPH oxidase and survival in chronic granulomatous disease. N Engl J Med. 2010;363(27):2600–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Ezekowitz RA, Dinauer MC, Jaffe HS, Orkin SH, Newburger PE. Partial correction of the phagocyte defect in patients with X-linked chronic granulomatous disease by subcutaneous interferon gamma. N Engl J Med. 1988;319(3):146–51.

    CAS  PubMed  Google Scholar 

  54. Condino-Neto A, Newburger PE. Interferon-gamma improves splicing efficiency of CYBB gene transcripts in an interferon-responsive variant of chronic granulomatous disease due to a splice site consensus region mutation. Blood. 2000;95(11):3548–54.

    CAS  PubMed  Google Scholar 

  55. Marciano BE, Wesley R, De Carlo ES, Anderson VL, Barnhart LA, Darnell D, et al. Long-term interferon-gamma therapy for patients with chronic granulomatous disease. Clin Infect Dis. 2004;39(5):692–9.

    CAS  PubMed  Google Scholar 

  56. Ott MG, Seger R, Stein S, Siler U, Hoelzer D, Grez M. Advances in the treatment of chronic granulomatous disease by gene therapy. Curr Gene Ther. 2007;7(3):155–61.

    CAS  PubMed  Google Scholar 

  57. Kilic SS, Hacimustafaoglu M, Boisson-Dupuis S, Kreins AY, Grant AV, Abel L, et al. A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J Pediatr. 2012;160(6):1055–7.

    PubMed Central  PubMed  Google Scholar 

  58. Mukherjee S, Thrasher AJ. Gene therapy for PIDs: progress, pitfalls and prospects. Gene. 2013;525(2):174–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Rezaei N, Moin M, Pourpak Z, Ramyar A, Izadyar M, Chavoshzadeh Z, et al. The clinical, immunohematological, and molecular study of Iranian patients with severe congenital neutropenia. J Clin Immunol. 2007;27(5):525–33.

    PubMed  Google Scholar 

  60. Wintergerst U, Rosenzweig SD, Abinun M, Malech HL, Holland SM, Rezaei N. Phagocytes defects. In: Rezaei N, Aghamohammadi A, Notarangelo LD, editors. Primary immunodeficiency diseases: definition, diagnosis and management. Heidelberg: Springer; 2008. p. 131–66.

    Google Scholar 

  61. Skokowa J, Germeshausen M, Zeidler C, Welte K. Severe congenital neutropenia: inheritance and pathophysiology. Curr Opin Hematol. 2007;14(1):22–8.

    PubMed  Google Scholar 

  62. Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol. 2011;29:399–413.

    CAS  PubMed  Google Scholar 

  63. Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96(7):2317–22.

    CAS  PubMed  Google Scholar 

  64. Salipante SJ, Benson KF, Luty J, Hadavi V, Kariminejad R, Kariminejad MH, et al. Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia. Hum Mutat. 2007;28(9):874–81.

    CAS  PubMed  Google Scholar 

  65. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schaffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86–92.

    CAS  PubMed  Google Scholar 

  66. Boztug K, Appaswamy G, Ashikov A, Schaffer AA, Salzer U, Diestelhorst J, et al. A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med. 2009;360(1):32–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Boztug K, Rosenberg PS, Dorda M, Banka S, Moulton T, Curtin J, et al. Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: novel genotypes and phenotypic variability in severe congenital neutropenia. J Pediatr. 2012;160(4):679 e2–83 e2.

    Google Scholar 

  68. Person RE, Li FQ, Duan Z, Benson KF, Wechsler J, Papadaki HA, et al. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. Nat Genet. 2003;34(3):308–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Devriendt K, Kim AS, Mathijs G, Frints SG, Schwartz M, Van Den Oord JJ, et al. Constitutively activating mutation in WASP causes X-linked severe congenital neutropenia. Nat Genet. 2001;27(3):313–7.

    CAS  PubMed  Google Scholar 

  70. Rezaei N, Farhoudi A, Ramyar A, Pourpak Z, Aghamohammadi A, Mohammadpour B, et al. Congenital neutropenia and primary immunodeficiency disorders: a survey of 26 Iranian patients. J Pediatr Hematol Oncol. 2005;27(7):351–6.

    PubMed  Google Scholar 

  71. Rezaei N, Farhoudi A, Pourpak Z, Aghamohammadi A, Moin M, Movahedi M, et al. Neutropenia in Iranian patients with primary immunodeficiency disorders. Haematologica. 2005;90(4):554–6.

    PubMed  Google Scholar 

  72. Rezaei N, Chavoshzadeh Z, Alaei OR, Sandrock I, Klein C. Association of HAX1 deficiency with neurological disorder. Neuropediatrics. 2008;38:261–3.

    Google Scholar 

  73. Rezaei N, Moazzami K, Aghamohammadi A, Klein C. Neutropenia and primary immunodeficiency diseases. Int Rev Immunol. 2009;28(5):335–66.

    CAS  PubMed  Google Scholar 

  74. Rezaei N, Aghamohammadi A, Ramyar A, Pan-Hammarstrom Q, Hammarstrom L. Severe congenital neutropenia or hyper-IgM syndrome? A novel mutation of CD40 ligand in a patient with severe neutropenia. Int Arch Allergy Immunol. 2008;147(3):255–9.

    PubMed  Google Scholar 

  75. Rezaei N, Aghamohammadi A, Moin M, Pourpak Z, Movahedi M, Gharagozlou M, et al. Frequency and clinical manifestations of patients with primary immunodeficiency disorders in Iran: update from the Iranian Primary Immunodeficiency Registry. J Clin Immunol. 2006;26(6):519–32.

    PubMed  Google Scholar 

  76. Dong F, Brynes RK, Tidow N, Welte K, Lowenberg B, Touw IP. Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. N Engl J Med. 1995;333(8):487–93.

    CAS  PubMed  Google Scholar 

  77. van de Vijver E, van den Berg TK, Kuijpers TW. Leukocyte adhesion deficiencies. Hematol Oncol Clin N Am. 2013;27(1):101–16. viii.

    Google Scholar 

  78. van de Vijver E, Maddalena A, Sanal O, Holland SM, Uzel G, Madkaikar M, et al. Hematologically important mutations: leukocyte adhesion deficiency (first update). Blood Cells Mol Dis. 2012;48(1):53–61.

    PubMed  Google Scholar 

  79. Etzioni A. Genetic etiologies of leukocyte adhesion defects. Curr Opin Immunol. 2009;21(5):481–6.

    CAS  PubMed  Google Scholar 

  80. Zimmerman GA. LAD syndromes: FERMT3 kindles the signal. Blood. 2009;113(19):4485–6.

    CAS  PubMed  Google Scholar 

  81. Casanova JL, Abel L. Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol. 2002;20:581–620.

    CAS  PubMed  Google Scholar 

  82. Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, et al. Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine (Baltimore). 2013;92(2):109–22.

    CAS  Google Scholar 

  83. de Beaucoudrey L, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S, Feinberg J, et al. Revisiting human IL-12Rbeta1 deficiency: a survey of 141 patients from 30 countries. Medicine (Baltimore). 2010;89(6):381–402.

    Google Scholar 

  84. Boisson-Dupuis S, El Baghdadi J, Parvaneh N, Bousfiha A, Bustamante J, Feinberg J, et al. IL-12Rbeta1 deficiency in two of fifty children with severe tuberculosis from Iran, Morocco, and Turkey. PLoS One. 2011;6(4):e18524.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Caragol I, Raspall M, Fieschi C, Feinberg J, Larrosa MN, Hernandez M, et al. Clinical tuberculosis in 2 of 3 siblings with interleukin-12 receptor beta1 deficiency. Clin Infect Dis. 2003;37(2):302–6.

    CAS  PubMed  Google Scholar 

  86. Tabarsi P, Marjani M, Mansouri N, Farnia P, Boisson-Dupuis S, Bustamante J, et al. Lethal tuberculosis in a previously healthy adult with IL-12 receptor deficiency. J Clin Immunol. 2011;31(4):537–9.

    PubMed  Google Scholar 

  87. Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J, et al. Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol. 2006;18(6):347–61.

    CAS  PubMed  Google Scholar 

  88. Kong XF, Vogt G, Itan Y, Macura-Biegun A, Szaflarska A, Kowalczyk D, et al. Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. Hum Mol Genet. 2013;22(4):769–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Hambleton S, Salem S, Bustamante J, Bigley V, Boisson-Dupuis S, Azevedo J, et al. IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med. 2011;365(2):127–38.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Bustamante J, Arias AA, Vogt G, Picard C, Galicia LB, Prando C, et al. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol. 2011;12(3):213–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Bogunovic D, Byun M, Durfee LA, Abhyankar A, Sanal O, Mansouri D, et al. Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science. 2012;337(6102):1684–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol. 2012;24(4):364–78.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med. 2006;203(7):1745–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Vogt G, Bustamante J, Chapgier A, Feinberg J, Boisson Dupuis S, Picard C, et al. Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation. J Exp Med. 2008;205(8):1729–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Sologuren I, Boisson-Dupuis S, Pestano J, Vincent QB, Fernandez-Perez L, Chapgier A, et al. Partial recessive IFN-gammaR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds. Hum Mol Genet. 2011;20(8):1509–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Bustamante J, Picard C, Boisson-Dupuis S, Abel L, Casanova JL. Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases. Ann N Y Acad Sci. 2011;1246:92–101.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Dorman SE, Picard C, Lammas D, Heyne K, van Dissel JT, Baretto R, et al. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet. 2004;364(9451):2113–21.

    CAS  PubMed  Google Scholar 

  98. MacLennan C, Fieschi C, Lammas DA, Picard C, Dorman SE, Sanal O, et al. Interleukin (IL)-12 and IL-23 are key cytokines for immunity against Salmonella in humans. J Infect Dis. 2004;190(10):1755–7.

    CAS  PubMed  Google Scholar 

  99. Moraes-Vasconcelos D, Grumach AS, Yamaguti A, Andrade ME, Fieschi C, de Beaucoudrey L, et al. Paracoccidioides brasiliensis disseminated disease in a patient with inherited deficiency in the beta1 subunit of the interleukin (IL)-12/IL-23 receptor. Clin Infect Dis. 2005;41(4):e31–7.

    PubMed  Google Scholar 

  100. Pedraza S, Lezana JL, Samarina A, Aldana R, Herrera MT, Boisson-Dupuis S, et al. Clinical disease caused by Klebsiella in 2 unrelated patients with interleukin 12 receptor beta1 deficiency. Pediatrics. 2010;126(4):e971-6.

    PubMed  Google Scholar 

  101. Sanal O, Turkkani G, Gumruk F, Yel L, Secmeer G, Tezcan I, et al. A case of interleukin-12 receptor beta-1 deficiency with recurrent leishmaniasis. Pediatr Infect Dis J. 2007;26(4):366–8.

    PubMed  Google Scholar 

  102. Alangari AA, Al-Zamil F, Al-Mazrou A, Al-Muhsen S, Boisson-Dupuis S, Awadallah S, et al. Treatment of disseminated mycobacterial infection with high-dose IFN-gamma in a patient with IL-12Rbeta1 deficiency. Clin Dev Immunol. 2011;2011:691956.

    PubMed Central  PubMed  Google Scholar 

  103. Moilanen P, Korppi M, Hovi L, Chapgier A, Feinberg J, Kong XF, et al. Successful hematopoietic stem cell transplantation from an unrelated donor in a child with interferon gamma receptor deficiency. Pediatr Infect Dis J. 2009;28(7):658–60.

    PubMed  Google Scholar 

  104. Fieschi C, Dupuis S, Picard C, Smith CI, Holland SM, Casanova JL. High levels of interferon gamma in the plasma of children with complete interferon gamma receptor deficiency. Pediatrics. 2001;107(4):E48.

    CAS  PubMed  Google Scholar 

  105. Koss M, Bolze A, Brendolan A, Saggese M, Capellini TD, Bojilova E, et al. Congenital asplenia in mice and humans with mutations in a Pbx/Nkx2-5/p15 module. Dev Cell. 2012;22(5):913–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Al Khatib S, Keles S, Garcia-Lloret M, Karakoc-Aydiner E, Reisli I, Artac H, et al. Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome. J Allergy Clin Immunol. 2009;124(2):342–8. 8 e1-5.

    PubMed Central  PubMed  Google Scholar 

  107. Kanthan R, Moyana T, Nyssen J. Asplenia as a cause of sudden unexpected death in childhood. Am J Forensic Med Pathol. 1999;20(1):57–9.

    CAS  PubMed  Google Scholar 

  108. Schutze GE, Mason Jr EO, Barson WJ, Kim KS, Wald ER, Givner LB, et al. Invasive pneumococcal infections in children with asplenia. Pediatr Infect Dis J. 2002;21(4):278–82.

    PubMed  Google Scholar 

  109. Lion C, Escande F, Burdin JC. Capnocytophaga canimorsus infections in human: review of the literature and cases report. Eur J Epidemiol. 1996;12(5):521–33.

    CAS  PubMed  Google Scholar 

  110. Waldman JD, Rosenthal A, Smith AL, Shurin S, Nadas AS. Sepsis and congenital asplenia. J Pediatr. 1977;90(4):555–9.

    CAS  PubMed  Google Scholar 

  111. Rogers ZR, Wang WC, Luo Z, Iyer RV, Shalaby-Rana E, Dertinger SD, et al. Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial. Blood. 2011;117(9):2614–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Nagel BH, Williams H, Stewart L, Paul J, Stumper O. Splenic state in surviving patients with visceral heterotaxy. Cardiol Young. 2005;15(5):469–73.

    PubMed  Google Scholar 

  113. Price VE, Blanchette VS, Ford-Jones EL. The prevention and management of infections in children with asplenia or hyposplenia. Infect Dis Clin N Am. 2007;21(3):697–710. viii–ix.

    Google Scholar 

  114. Dempsey PW, Allison MED, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science. 1996;271:348–50.

    CAS  PubMed  Google Scholar 

  115. Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of Neisserial and other infections in an immune deficiency. Medicine. 1984;63(5):243–73.

    CAS  PubMed  Google Scholar 

  116. Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev. 1991;4(3):359–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Figueroa J, Andreoni J, Densen P. Complement deficiency states and meningococcal disease. Immunol Res. 1993;12(3):295–311.

    CAS  PubMed  Google Scholar 

  118. Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54.

    PubMed Central  PubMed  Google Scholar 

  119. Kwan A, Church JA, Cowan MJ, Agarwal R, Kapoor N, Kohn DB, et al. Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years. J Allergy Clin Immunol. 2013;132(1):140–50.

    PubMed  Google Scholar 

  120. Buckley RH. The long quest for neonatal screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2012;129(3):597–604. quiz 5–6.

    PubMed Central  PubMed  Google Scholar 

  121. Al-Herz W, Naguib KK, Notarangelo LD, Geha RS, Alwadaani A. Parental consanguinity and the risk of primary immunodeficiency disorders: report from the Kuwait National Primary Immunodeficiency Disorders Registry. Int Arch Allergy Immunol. 2011;154(1):76–80.

    PubMed  Google Scholar 

  122. Rosen FS. Severe combined immunodeficiency: a pediatric emergency. J Pediatr. 1997;130(3):345–6.

    CAS  PubMed  Google Scholar 

  123. Griffith LM, Cowan MJ, Notarangelo LD, Puck JM, Buckley RH, Candotti F, et al. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J Allergy Clin Immunol. 2009;124(6):1152 e12–60 e12.

    Google Scholar 

  124. Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.

    CAS  PubMed  Google Scholar 

  125. Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114(17):3524–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Gennery AR, Slatter MA, Grandin L, Taupin P, Cant AJ, Veys P, et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010;126(3):602 e1-11–10 e1-11.

    Google Scholar 

  127. Felgentreff K, Perez-Becker R, Speckmann C, Schwarz K, Kalwak K, Markelj G, et al. Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency. Clin Immunol. 2011;141(1):73–82.

    CAS  PubMed  Google Scholar 

  128. Roifman CM, Somech R, Kavadas F, Pires L, Nahum A, Dalal I, et al. Defining combined immunodeficiency. J Allergy Clin Immunol. 2012;130(1):177–83.

    CAS  PubMed  Google Scholar 

  129. van der Burg M, Gennery AR. Educational paper. The expanding clinical and immunological spectrum of severe combined immunodeficiency. Eur J Pediatr. 2011;170(5):561–71.

    PubMed Central  PubMed  Google Scholar 

  130. Liston A, Enders A, Siggs OM. Unravelling the association of partial T-cell immunodeficiency and immune dysregulation. Nat Rev Immunol. 2008;8(7):545–58.

    CAS  PubMed  Google Scholar 

  131. Notarangelo LD. Functional T cell immunodeficiencies (with T cells present). Annu Rev Immunol. 2013;31(1):195–225.

    Google Scholar 

  132. Gossage DL, Buckley RH. Prevalence of lymphocytopenia in severe combined immunodeficiency. N Engl J Med. 1990;323(20):1422–3.

    CAS  PubMed  Google Scholar 

  133. Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2005;115(2):391–8.

    PubMed  Google Scholar 

  134. Morinishi Y, Imai K, Nakagawa N, Sato H, Horiuchi K, Ohtsuka Y, et al. Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards. J Pediatr. 2009;155(6):829–33.

    CAS  PubMed  Google Scholar 

  135. Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49(1–3):25–43.

    PubMed Central  PubMed  Google Scholar 

  136. Routes JM, Grossman WJ, Verbsky J, Laessig RH, Hoffman GL, Brokopp CD, et al. Statewide newborn screening for severe T-cell lymphopenia. JAMA. 2009;302(22):2465–70.

    CAS  PubMed  Google Scholar 

  137. Verbsky JW, Baker MW, Grossman WJ, Hintermeyer M, Dasu T, Bonacci B, et al. Newborn screening for severe combined immunodeficiency; the Wisconsin experience (2008–2011). J Clin Immunol. 2012;32(1):82–8.

    PubMed  Google Scholar 

  138. Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of class-switch recombination. J Allergy Clin Immunol. 2006;117(4):855–64.

    CAS  PubMed  Google Scholar 

  139. Roulland S, Suarez F, Hermine O, Nadel B. Pathophysiological aspects of memory B-cell development. Trends Immunol. 2008;29(1):25–33.

    CAS  PubMed  Google Scholar 

  140. Jain A, Atkinson TP, Lipsky PE, Slater JE, Nelson DL, Strober W. Defects of T-cell effector function and post-thymic maturation in X-linked hyper-IgM syndrome. J Clin Invest. 1999;103(8):1151–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Lee WI, Torgerson TR, Schumacher MJ, Yel L, Zhu Q, Ochs HD. Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome. Blood. 2005;105(5):1881–90.

    CAS  PubMed  Google Scholar 

  142. 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 (Baltimore). 2003;82(6):373–84.

    CAS  Google Scholar 

  143. Allen RC, Armitage RJ, Conley ME, Rosenblatt H, Jenkins NA, Copeland NG, et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993;259(5097):990–3.

    CAS  PubMed  Google Scholar 

  144. Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, et al. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993;72(2):291–300.

    CAS  PubMed  Google Scholar 

  145. DiSanto JP, Bonnefoy JY, Gauchat JF, Fischer A, de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993;361(6412):541–3.

    CAS  PubMed  Google Scholar 

  146. 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.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S, et al. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993;361(6412):539–41.

    CAS  PubMed  Google Scholar 

  148. Noelle RJ. The role of gp39 (CD40L) in immunity. Clin Immunol Immunopathol. 1995;76(3 Pt 2):S203–7.

    CAS  PubMed  Google Scholar 

  149. Facchetti F, Appiani C, Salvi L, Levy J, Notarangelo LD. Immunohistologic analysis of ineffective CD40-CD40 ligand interaction in lymphoid tissues from patients with X-linked immunodeficiency with hyper-IgM. Abortive germinal center cell reaction and severe depletion of follicular dendritic cells. J Immunol. 1995;154(12):6624–33.

    CAS  PubMed  Google Scholar 

  150. 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 Pt 1):47–54.

    CAS  PubMed  Google Scholar 

  151. Cabral-Marques O, Schimke LF, Pereira PV, Falcai A, de Oliveira JB, Hackett MJ, et al. Expanding the clinical and genetic spectrum of human CD40L deficiency: the occurrence of paracoccidioidomycosis and other unusual infections in Brazilian patients. J Clin Immunol. 2012;32(2):212–20.

    PubMed  Google Scholar 

  152. Notarangelo LD, Lanzi G, Toniati P, Giliani S. Immunodeficiencies due to defects of class-switch recombination. Immunol Res. 2007;38(1–3):68–77.

    CAS  PubMed  Google Scholar 

  153. Wolska-Kusnierz B, Bajer A, Caccio S, Heropolitanska-Pliszka E, Bernatowska E, Socha P, et al. Cryptosporidium infection in patients with primary immunodeficiencies. J Pediatr Gastroenterol Nutr. 2007;45(4):458–64.

    PubMed  Google Scholar 

  154. Jesus AA, Duarte AJ, Oliveira JB. Autoimmunity in hyper-IgM syndrome. J Clin Immunol. 2008;28 Suppl 1:S62–6.

    CAS  PubMed  Google Scholar 

  155. Hayward AR, Levy J, Facchetti F, Notarangelo L, Ochs HD, Etzioni A, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol. 1997;158(2):977–83.

    CAS  PubMed  Google Scholar 

  156. Banatvala N, Davies J, Kanariou M, Strobel S, Levinsky R, Morgan G. Hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM syndrome): a case series review. Arch Dis Child. 1994;71(2):150–2.

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Thomas C, de Saint Basile G, Le Deist F, Theophile D, Benkerrou M, Haddad E, et al. Brief report: correction of X-linked hyper-IgM syndrome by allogeneic bone marrow transplantation. N Engl J Med. 1995;333(7):426–9.

    CAS  PubMed  Google Scholar 

  158. Bordigoni P, Auburtin B, Carret AS, Schuhmacher A, Humbert JC, Le Deist F, et al. Bone marrow transplantation as treatment for X-linked immunodeficiency with hyper-IgM. Bone Marrow Transplant. 1998;22(11):1111–4.

    CAS  PubMed  Google Scholar 

  159. Hadzic N, Pagliuca A, Rela M, Portmann B, Jones A, Veys P, et al. Correction of the hyper-IgM syndrome after liver and bone marrow transplantation. N Engl J Med. 2000;342(5):320–4.

    CAS  PubMed  Google Scholar 

  160. Duplantier JE, Seyama K, Day NK, Hitchcock R, Nelson Jr RP, Ochs HD, et al. Immunologic reconstitution following bone marrow transplantation for X-linked hyper IgM syndrome. Clin Immunol. 2001;98(3):313–8.

    CAS  PubMed  Google Scholar 

  161. Khawaja K, Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone marrow transplantation for CD40 ligand deficiency: a single centre experience. Arch Dis Child. 2001;84(6):508–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Tomizawa D, Imai K, Ito S, Kajiwara M, Minegishi Y, Nagasawa M, et al. Allogeneic hematopoietic stem cell transplantation for seven children with X-linked hyper-IgM syndrome: a single center experience. Am J Hematol. 2004;76(1):33–9.

    PubMed  Google Scholar 

  163. Jacobsohn DA, Emerick KM, Scholl P, Melin-Aldana H, O’Gorman M, Duerst R, et al. Nonmyeloablative hematopoietic stem cell transplant for X-linked hyper-immunoglobulin m syndrome with cholangiopathy. Pediatrics. 2004;113(2):e122–7.

    PubMed  Google Scholar 

  164. Tsuji Y, Imai K, Kajiwara M, Aoki Y, Isoda T, Tomizawa D, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. 2006;37(5):469–77.

    CAS  PubMed  Google Scholar 

  165. Kikuta A, Ito M, Mochizuki K, Akaihata M, Nemoto K, Sano H, et al. Nonmyeloablative stem cell transplantation for nonmalignant diseases in children with severe organ dysfunction. Bone Marrow Transplant. 2006;38(10):665–9.

    CAS  PubMed  Google Scholar 

  166. Sato T, Kobayashi R, Toita N, Kaneda M, Hatano N, Iguchi A, et al. Stem cell transplantation in primary immunodeficiency disease patients. Pediatr Int. 2007;49(6):795–800.

    CAS  PubMed  Google Scholar 

  167. Gennery AR, Khawaja K, Veys P, Bredius RG, Notarangelo LD, Mazzolari E, et al. Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993–2002. Blood. 2004;103(3):1152–7.

    CAS  PubMed  Google Scholar 

  168. Jain A, Kovacs JA, Nelson DL, Migueles SA, Pittaluga S, Fanslow W, et al. Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand. Blood. 2011;118(14):3811–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Durandy A, Revy P, Imai K, Fischer A. Hyper-immunoglobulin M syndromes caused by intrinsic B-lymphocyte defects. Immunol Rev. 2005;203:67–79.

    CAS  PubMed  Google Scholar 

  170. Callard RE, Smith SH, Herbert J, Morgan G, Padayachee M, Lederman S, et al. CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers. J Immunol. 1994;153(7):3295–306.

    CAS  PubMed  Google Scholar 

  171. Conley ME, Larche M, Bonagura VR, Lawton 3rd AR, Buckley RH, Fu SM, et al. Hyper IgM syndrome associated with defective CD40-mediated B cell activation. J Clin Invest. 1994;94(4):1404–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Revy P, Geissmann F, Debre M, Fischer A, Durandy A. Normal CD40-mediated activation of monocytes and dendritic cells from patients with hyper-IgM syndrome due to a CD40 pathway defect in B cells. Eur J Immunol. 1998;28(11):3648–54.

    CAS  PubMed  Google Scholar 

  173. Quartier P, Bustamante J, Sanal O, Plebani A, Debre 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.

    CAS  PubMed  Google Scholar 

  174. Gormand F, Briere F, Peyrol S, Raccurt M, Durand I, Ait-Yahia S, et al. CD40 expression by human bronchial epithelial cells. Scand J Immunol. 1999;49(4):355–61.

    CAS  PubMed  Google Scholar 

  175. 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.

    PubMed  Google Scholar 

  176. Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M, et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A. 2001;98(22):12614–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Karaca NE, Forveille M, Aksu G, Durandy A, Kutukculer N. Hyper-immunoglobulin M syndrome type 3 with normal CD40 cell surface expression. Scand J Immunol. 2012;76(1):21–5.

    CAS  PubMed  Google Scholar 

  178. Kutukculer N, Aksoylar S, Kansoy S, Cetingul N, Notarangelo LD. Outcome of hematopoietic stem cell transplantation in hyper-IgM syndrome caused by CD40 deficiency. J Pediatr. 2003;143(1):141–2.

    PubMed  Google Scholar 

  179. Mazzolari E, Lanzi G, Forino C, Lanfranchi A, Aksu G, Ozturk C, et al. First report of successful stem cell transplantation in a child with CD40 deficiency. Bone Marrow Transplant. 2007;40(3):279–81.

    CAS  PubMed  Google Scholar 

  180. Ta VT, Nagaoka H, Catalan N, Durandy A, Fischer A, Imai K, et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nat Immunol. 2003;4(9):843–8.

    CAS  PubMed  Google Scholar 

  181. Imai K, Catalan N, Plebani A, Marodi L, Sanal O, Kumaki S, et al. Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination. J Clin Invest. 2003;112(1):136–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Imai K, Zhu Y, Revy P, Morio T, Mizutani S, Fischer A, et al. Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2. Clin Immunol. 2005;115(3):277–85.

    CAS  PubMed  Google Scholar 

  183. Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N, et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol. 2003;4(10):1023–8.

    CAS  PubMed  Google Scholar 

  184. Kavli B, Andersen S, Otterlei M, Liabakk NB, Imai K, Fischer A, et al. B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil. J Exp Med. 2005;201(12):2011–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  185. 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 p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.

    CAS  PubMed  Google Scholar 

  186. Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9(6):722–8.

    CAS  PubMed  Google Scholar 

  187. Stray-Pedersen A, Abrahamsen TG, Froland SS. Primary immunodeficiency diseases in Norway. J Clin Immunol. 2000;20(6):477–85.

    CAS  PubMed  Google Scholar 

  188. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, et al. X-linked agammaglobulinemia: report on a United States registry of 201 patients. Medicine (Baltimore). 2006;85(4):193–202.

    Google Scholar 

  189. Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993;72(2):279–90.

    CAS  PubMed  Google Scholar 

  190. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361(6409):226–33.

    CAS  PubMed  Google Scholar 

  191. Lederman HM, Winkelstein JA. X-linked agammaglobulinemia: an analysis of 96 patients. Medicine (Baltimore). 1985;64(3):145–56.

    CAS  Google Scholar 

  192. Brosens LA, Tytgat KM, Morsink FH, Sinke RJ, Ten Berge IJ, Giardiello FM, et al. Multiple colorectal neoplasms in X-linked agammaglobulinemia. Clin Gastroenterol Hepatol. 2008;6(1):115–9.

    PubMed  Google Scholar 

  193. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93(3):190–7.

    CAS  PubMed  Google Scholar 

  194. Conley ME. Genetics of hypogammaglobulinemia: what do we really know? Curr Opin Immunol. 2009;21(5):466–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E, et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K. J Exp Med. 2012;209(3):463–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  196. McKinnon PJ. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol. 2012;7:303–21.

    CAS  PubMed  Google Scholar 

  197. Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366(7):636–46.

    CAS  PubMed  Google Scholar 

  198. Dehkordy SF, Aghamohammadi A, Ochs HD, Rezaei N. Primary immunodeficiency diseases associated with neurologic manifestations. J Clin Immunol. 2012;32(1):1–24.

    PubMed  Google Scholar 

  199. Seif AE. Pediatric leukemia predisposition syndromes: clues to understanding leukemogenesis. Cancer Genet. 2011;204(5):227–44.

    PubMed  Google Scholar 

  200. Al-Maawali A, Blaser S, Yoon G. Diagnostic approach to childhood-onset cerebellar atrophy: a 10-year retrospective study of 300 patients. J Child Neurol. 2012;27(9):1121–32.

    PubMed Central  PubMed  Google Scholar 

  201. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2005;94(5 Suppl 1):S1–S63.

    Google Scholar 

  202. Albert MH, Notarangelo LD, Ochs HD. Clinical spectrum, pathophysiology and treatment of the Wiskott-Aldrich syndrome. Curr Opin Hematol. 2011;18(1):42–48.

    Google Scholar 

  203. Snapper SB, Rosen FS. The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization. Annu Rev Immunol. 1999;17:905–29.

    CAS  PubMed  Google Scholar 

  204. Derry JM, Ochs HD, Francke U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell. 1994;79(5):following 922.

    CAS  PubMed  Google Scholar 

  205. Stewart DM, Treiber-Held S, Kurman CC, Facchetti F, Notarangelo LD, Nelson DL. Studies of the expression of the Wiskott-Aldrich syndrome protein. J Clin Invest. 1996;97(11):2627–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  206. Thrasher AJ, Burns SO. WASP: a key immunological multitasker. Nat Rev Immunol. 2010;10(3):182–92.

    CAS  PubMed  Google Scholar 

  207. Becker-Herman S, Meyer-Bahlburg A, Schwartz MA, Jackson SW, Hudkins KL, Liu C, et al. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J Exp Med. 2011;208(10):2033–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  208. Recher M, Burns SO, de la Fuente MA, Volpi S, Dahlberg C, Walter JE, et al. B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice. Blood. 2012;119(12):2819–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  209. Bouma G, Mendoza-Naranjo A, Blundell MP, de Falco E, Parsley KL, Burns SO, et al. Cytoskeletal remodeling mediated by WASp in dendritic cells is necessary for normal immune synapse formation and T-cell priming. Blood. 2011;118(9):2492–501.

    CAS  PubMed  Google Scholar 

  210. Worth AJ, Metelo J, Bouma G, Moulding D, Fritzsche M, Vernay B, et al. Disease-associated missense mutations in the EVH1 domain disrupt intrinsic WASp function causing dysregulated actin dynamics and impaired dendritic cell migration. Blood. 2013;121(1):72–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr. 1994;125(6 Pt 1):876–85.

    CAS  PubMed  Google Scholar 

  212. Dupuis-Girod S, Medioni J, Haddad E, Quartier P, Cavazzana-Calvo M, Le Deist F, et al. Autoimmunity in Wiskott-Aldrich syndrome: risk factors, clinical features, and outcome in a single-center cohort of 55 patients. Pediatrics. 2003;111(5 Pt 1):e622–7.

    PubMed  Google Scholar 

  213. Notarangelo LD, Mazza C, Giliani S, D’Aria C, Gandellini F, Ravelli C, et al. Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia. Blood. 2002;99(6):2268–9.

    CAS  PubMed  Google Scholar 

  214. Ochs HD, Slichter SJ, Harker LA, Von Behrens WE, Clark RA, Wedgwood RJ. The Wiskott-Aldrich syndrome: studies of lymphocytes, granulocytes, and platelets. Blood. 1980;55(2):243–52.

    CAS  PubMed  Google Scholar 

  215. Blaese RM, Strober W, Brown RS, Waldmann TA. The Wiskott-Aldrich syndrome. A disorder with a possible defect in antigen processing or recognition. Lancet. 1968;1(7551):1056–61.

    CAS  PubMed  Google Scholar 

  216. Cooper MD, Chae HP, Lowman JT, Krivit W, Good RA. Wiskott-Aldrich syndrome. An immunologic deficiency disease involving the afferent limb of immunity. Am J Med. 1968;44(4):499–513.

    CAS  PubMed  Google Scholar 

  217. Siminovitch KA, Greer WL, Novogrodsky A, Axelsson B, Somani AK, Peacocke M. A diagnostic assay for the Wiskott-Aldrich syndrome and its variant forms. J Investig Med. 1995;43(2):159–69.

    CAS  PubMed  Google Scholar 

  218. Filipovich AH, Stone JV, Tomany SC, Ireland M, Kollman C, Pelz CJ, et al. Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program. Blood. 2001;97(6):1598–603.

    CAS  PubMed  Google Scholar 

  219. Moratto D, Giliani S, Bonfim C, Mazzolari E, Fischer A, Ochs HD, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980–2009: an international collaborative study. Blood. 2011;118(6):1675–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science. 2013;341(6148):1233151.

    PubMed  Google Scholar 

  221. Albert MH, Bittner TC, Nonoyama S, Notarangelo LD, Burns S, Imai K, et al. X-linked thrombocytopenia (XLT) due to WAS mutations: clinical characteristics, long-term outcome, and treatment options. Blood. 2010;115(16):3231–8.

    CAS  PubMed  Google Scholar 

  222. Mahlaoui N, Pellier I, Mignot C, Jais JP, Bilhou-Nabera C, Moshous D, et al. Characteristics and outcome of early-onset, severe forms of Wiskott-Aldrich syndrome. Blood. 2013;121(9):1510–6.

    CAS  PubMed  Google Scholar 

  223. Imai K, Morio T, Zhu Y, Jin Y, Itoh S, Kajiwara M, et al. Clinical course of patients with WASP gene mutations. Blood. 2004;103(2):456–64.

    CAS  PubMed  Google Scholar 

  224. Jin Y, Mazza C, Christie JR, Giliani S, Fiorini M, Mella P, et al. Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood. 2004;104(13):4010–9.

    CAS  PubMed  Google Scholar 

  225. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, et al. Hyper-IgE syndrome with recurrent infections–an autosomal dominant multisystem disorder. N Engl J Med. 1999;340(9):692–702.

    CAS  PubMed  Google Scholar 

  226. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448(7157):1058–62.

    CAS  PubMed  Google Scholar 

  227. Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, et al. Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med. 2008;205(7):1551–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  228. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity. 2006;25(5):745–55.

    CAS  PubMed  Google Scholar 

  229. Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med. 2009;361(21):2046–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  230. Jabara HH, McDonald DR, Janssen E, Massaad MJ, Ramesh N, Borzutzky A, et al. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol. 2012;13(6):612–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  231. Bittner TC, Pannicke U, Renner ED, Notheis G, Hoffmann F, Belohradsky BH, et al. Successful long-term correction of autosomal recessive hyper-IgE syndrome due to DOCK8 deficiency by hematopoietic stem cell transplantation. Klin Padiatr. 2010;222(6):351–5.

    CAS  PubMed  Google Scholar 

  232. Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant. 2000;25(12):1303–5.

    CAS  PubMed  Google Scholar 

  233. Gatz SA, Benninghoff U, Schutz C, Schulz A, Honig M, Pannicke U, et al. Curative treatment of autosomal-recessive hyper-IgE syndrome by hematopoietic cell transplantation. Bone Marrow Transplant. 2011;46(4):552–6.

    CAS  PubMed  Google Scholar 

  234. Digilio MC, Marino B, Giannotti A, Dallapiccola B. Chromosome 22q11 microdeletion and isolated conotruncal heart defects [letter; comment]. Arch Dis Child. 1997;76(1):79–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  235. Goldmuntz E, Clark BJ, Mitchell LE, Jawad AF, Cuneo BF, Reed L, et al. Frequency of 22q11 deletions in patients with conotruncal defects. J Am Coll Cardiol. 1998;32(2):492–8.

    CAS  PubMed  Google Scholar 

  236. Marino B, Digilio MC, Toscano A, Anaclerio S, Gianotti A, Feltri C, et al. Anatomic patterns of conotruncal defects associated with deletion 22q11. Genet Med. 2001;3:45–8.

    CAS  PubMed  Google Scholar 

  237. Bale PM, Sotelo-Avila C. Maldescent of the thymus: 34 necropsy and 10 surgical cases, including 7 thymuses medial to the mandible. Pediatr Pathol. 1993;13(2):181–90.

    CAS  PubMed  Google Scholar 

  238. Jawad AF, Luning Prak E, Boyer J, McDonald-McGinn D, Zackai E, McDonald K, et al. A prospective study of influenza vaccination and a comparison of immunologic parameters in children and adults with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Clin Immunol. 2011;31(6):927–35.

    Google Scholar 

  239. Jawad AF, McDonald-McGinn DM, Zackai E, Sullivan KE. Immunologic features of chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). J Pediatr. 2001;139:715–23.

    CAS  PubMed  Google Scholar 

  240. Chinen J, Rosenblatt HM, Smith EO, Shearer WT, Noroski LM. Long-term assessment of T-cell populations in DiGeorge syndrome. J Allergy Clin Immunol. 2003;111(3):573–9.

    PubMed  Google Scholar 

  241. Finocchi A, Di Cesare S, Romiti ML, Capponi C, Rossi P, Carsetti R, et al. Humoral immune responses and CD27+ B cells in children with DiGeorge syndrome (22q11.2 deletion syndrome). Pediatr Allergy Immunol. 2006;17(5):382–8.

    CAS  PubMed  Google Scholar 

  242. Gennery AR, Barge D, O’Sullivan JJ, Flood TJ, Abinun M, Cant AJ. Antibody deficiency and autoimmunity in 22q11.2 deletion syndrome. Arch Dis Child. 2002;86(6):422–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  243. Patel K, Akhter J, Kobrynski L, Gathman B, Davis O, Sullivan KE. Immunoglobulin deficiencies: the B-lymphocyte side of digeorge syndrome. J Pediatr. 2012;161(5):950 e1–3 e1.

    Google Scholar 

  244. McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine (Baltimore). 2011;90(1):1–18.

    Google Scholar 

  245. Markert ML, Sarzotti M, Ozaki DA, Sempowski GD, Rhein ME, Hale LP, et al. Thymus transplantation in complete DiGeorge syndrome: immunologic and safety evaluations in 12 patients. Blood. 2003;102(3):1121–30.

    CAS  PubMed  Google Scholar 

  246. Staple L, Andrews T, McDonald-McGinn D, Zackai E, Sullivan KE. Allergies in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome) and patients with chronic granulomatous disease. Pediatr Allergy Immunol. 2005;16(3):226–30.

    PubMed  Google Scholar 

  247. Gambineri E, Torgerson TR. Genetic disorders with immune dysregulation. Cell Mol Life Sci. 2012;69(1):49–58.

    CAS  PubMed  Google Scholar 

  248. Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol. 2013;131(6):1611–23.

    CAS  PubMed  Google Scholar 

  249. Bennett CL, Brunkow ME, Ramsdell F, O’Briant KC, Zhu Q, Fuleihan RL, et al. A rare polyadenylation signal mutation of the FOXP3 gene (AAUAAA-->AAUGAA) leads to the IPEX syndrome. Immunogenetics. 2001;53(6):435–9.

    CAS  PubMed  Google Scholar 

  250. Torgerson TR, Linane A, Moes N, Anover S, Mateo V, Rieux-Laucat F, et al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology. 2007;132(5):1705–17.

    CAS  PubMed  Google Scholar 

  251. d’Hennezel E, Bin Dhuban K, Torgerson T, Piccirillo CA. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2012;49(5):291–302.

    PubMed  Google Scholar 

  252. Lucas KG, Ungar D, Comito M, Bayerl M, Groh B. Submyeloablative cord blood transplantation corrects clinical defects seen in IPEX syndrome. Bone Marrow Transplant. 2007;39(1):55–6.

    CAS  PubMed  Google Scholar 

  253. Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007;109(1):383–5.

    CAS  PubMed  Google Scholar 

  254. Seidel MG, Fritsch G, Lion T, Jurgens B, Heitger A, Bacchetta R, et al. Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood. 2009;113(22):5689–91.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. Ann Puel, Dr. Shen-Ying Zhang and Pr. Jean-Laurent Casanova for helpful discussions and advice and Dana Gudel and Audrey Harrington for expert secretarial assistance and editing.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Medical College of Wisconsin, and Children’s Research Institute, Milwaukee, WI, 53226-4874, USA

    John Routes

  2. Department of Pediatric Immunology, BMT Unit, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

    Mario Abinun

  3. Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait

    Waleed Al-Herz

  4. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale, Paris, France

    Jacinta Bustamante

  5. Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    Antonio Condino-Neto

  6. Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9063, USA

    Maria Teresa De La Morena

  7. Department of Pediatrics, Rambam Medical Centre and B. Rappaport School of Medicine, Technion, Haifa, Israel

    Amos Etzioni

  8. Department of Sciences for Woman and Child’s Health, Anna Meyer Children’s Hospital, Haematology-Oncology Department, BMT Unit, University of Florence, Viale Gaetano Pieraccini, 24, 50139, Florence, Italy

    Eleonora Gambineri

  9. Department of Pediatrics and Department of Microbiology and Immunology, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada

    Elie Haddad

  10. Department of Pediatrics, Emory University, Atlanta, GA, USA

    Lisa Kobrynski

  11. Department of Microbiology and Immunology and Department of Pediatrics, University of Montreal, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada

    Francoise Le Deist

  12. Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan

    Shigeaki Nonoyama

  13. Instituto de Medicina Integral Prof. Fernando Figueira-IMIP, Recife, PE, Brazil

    Joao Bosco Oliveira

  14. Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA

    Elena Perez

  15. Study Center of Primary Immunodeficiencies, Assistance Publique Hôpitaux de Paris, Necker Hospital, 75015, Paris, France

    Capucine Picard

  16. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Imagine Institute, Necker Medical School, Paris Descartes University, Paris, France, EU

    Capucine Picard

  17. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran, Iran

    Nima Rezaei

  18. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

  19. Division of Allergy and Immunology, Duke University School of Medicine, DUMC Box 2644, 203 Research Dr. Room 133B MSRB 1, Durham, NC, 27710, USA

    John Sleasman

  20. Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA, 19104-4399, USA

    Kathleen E. Sullivan

  21. University of Washington School of Medicine, 1900 9th Ave., C9S-7, Seattle, WA, 98101-1304, USA

    Troy Torgerson

  22. Medical College of Wisconsin, MACC Fund Research Center, Room 5064, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA

    John Routes

Authors
  1. John Routes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mario Abinun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Waleed Al-Herz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacinta Bustamante
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonio Condino-Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria Teresa De La Morena
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Amos Etzioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eleonora Gambineri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elie Haddad
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Lisa Kobrynski
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Francoise Le Deist
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shigeaki Nonoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Joao Bosco Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Elena Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Capucine Picard
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Nima Rezaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. John Sleasman
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kathleen E. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Troy Torgerson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Routes.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Routes, J., Abinun, M., Al-Herz, W. et al. ICON: The Early Diagnosis of Congenital Immunodeficiencies. J Clin Immunol 34, 398–424 (2014). https://doi.org/10.1007/s10875-014-0003-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-014-0003-x

Keywords

  • Primary immunodeficiencies
  • combined immunodeficiencies
  • severe combined immunodeficiencies
  • diagnosis
  • treatment
  • consensus
  • global-consensus