Skip to main content

Advertisement

SpringerLink
Log in

Immunodeficiencies Associated with Abnormal Newborn Screening for T Cell and B Cell Lymphopenia

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Newborn screening for SCID has revealed the association of low T cells with a number of unexpected syndromes associated with low T cells, some of which were not appreciated to have this feature. This review will discuss diagnostic approaches and the features of some of the syndromes likely to be encountered following newborn screening for immune deficiencies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Bousfiha A, Jeddane L, Al-Herz W, Ailal F, Casanova JL, Chatila T, et al. The 2015 IUIS phenotypic classification for primary Immunodeficiencies. J Clin Immunol. 2015;35(8):727–38.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kwan A, Abraham RS, 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(7):729–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Borte S, von Döbeln U, Fasth A, Wang N, Janzi M, Winiarski J, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012;119(11):2552–5.

    Article  CAS  PubMed  Google Scholar 

  4. Chiarini M, Zanotti C, Serana F, Sottini A, Bertoli D, Caimi L, et al. T-cell receptor and K-deleting recombination excision circles in newborn screening of T- and B-cell defects: review of the literature and future challenges. J Public Health Res. 2013;2(1):9–16.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  6. Adeli MM, Buckley RH. Why newborn screening for severe combined immunodeficiency is essential: a case report. Pediatrics. 2010;126(2):e465–9.

    Article  PubMed  Google Scholar 

  7. Comeau AM, Hale JE, Pai SY, Bonilla FA, Notarangelo LD, Pasternack MS, et al. Guidelines for implementation of population-based newborn screening for severe combined immunodeficiency. J Inherit Metab Dis. 2010;33(Suppl 2):S273–81.

    Article  PubMed  Google Scholar 

  8. Chan K, Davis J, Pai SY, Bonilla FA, Puck JM, Apkon M. A Markov model to analyze cost-effectiveness of screening for severe combined immunodeficiency (SCID). Mol Genet Metab. 2011;104(3):383–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chan A, Scalchunes C, Boyle M, Puck JM. Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey. Clin Immunol. 2011;138(1):3–8.

    Article  CAS  PubMed  Google Scholar 

  10. Brown L, Xu-Bayford J, Allwood Z, Slatter M, Cant A, Davies EG, et al. Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. Blood. 2011;117(11):3243–6.

    Article  CAS  PubMed  Google Scholar 

  11. Myers LA, Patel DD, Puck JM, Buckley RH. Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood. 2002;99(3):872–8.

    Article  CAS  PubMed  Google Scholar 

  12. 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):602–10.

    Article  PubMed  Google Scholar 

  13. Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014;371(5):434–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Puck JM. Laboratory technology for population-based screening for severe combined immunodeficiency in neonates: the winner is T-cell receptor excision circles. J Allergy Clin Immunol. 2012;129(3):607–16.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  16. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for primary immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gruber TA, Shah AJ, Hernandez M, Crooks GM, Abdel-Azim H, Gupta S, et al. Clinical and genetic heterogeneity in Omenn syndrome and severe combined immune deficiency. Pediatr Transplant. 2009;13(2):244–50.

    Article  PubMed  Google Scholar 

  19. Punwani D, Zhang Y, Yu J, Cowan M, Rana S, Kwan A, et al. Multisystem anomalies in severe combined immune deficiency with mutant BCL11B. N Engl J Med. 2016;375(22):2165–76.

    Article  CAS  PubMed  Google Scholar 

  20. Vogel BH, Bonagura V, Weinberg GA, Ballow M, Isabelle J, DiAntonio L, et al. Newborn screening for SCID in New York state: experience from the first two years. J Clin Immunol. 2014;34(3):289–303.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  PubMed  Google Scholar 

  22. Knutsen AP, Baker MW, Markert ML. Interpreting low T-cell receptor excision circles in newborns with DiGeorge anomaly: importance of assessing naive T-cell markers. J Allergy Clin Immunol. 2011;128(6):1375–6.

    Article  PubMed  Google Scholar 

  23. Goodship J, Cross I, LiLing J, Wren C. A population study of chromosome 22q11 deletions in infancy. Arch Dis Child. 1998;79(4):348–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tezenas Du Montcel S, Mendizabai H, Ayme S, Levy A, Philip N. Prevalence of 22q11 microdeletion. J Med Genet. 1996;33(8):719.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kobrynski LJ, Sullivan KE. Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes. Lancet. 2007;370(9596):1443–52.

    Article  CAS  PubMed  Google Scholar 

  26. Lindsay EA, Botta A, Jurecic V, Carattini-Rivera S, Cheah YC, Rosenblatt HM, et al. Congenital heart disease in mice deficient for the DiGeorge syndrome region. Nature. 1999;401(6751):379–83.

    CAS  PubMed  Google Scholar 

  27. Markert ML. Treatment of infants with complete DiGeorge anomaly. J Allergy Clin Immunol. 2008;121(4):1063. author reply -4

    Article  PubMed  Google Scholar 

  28. Markert ML, Hummell DS, Rosenblatt HM, Schiff SE, Harville TO, Williams LW, et al. Complete DiGeorge syndrome: persistence of profound immunodeficiency. J Pediatr. 1998;132(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  29. Markert ML, Alexieff MJ, Li J, Sarzotti M, Ozaki DA, Devlin BH, et al. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases. Journal of Allergy & Clinical Immunology. 2004;113(4):734–41.

    Article  CAS  Google Scholar 

  30. Selim MA, Markert ML, Burchette JL, Herman CM, Turner JW. The cutaneous manifestations of atypical complete DiGeorge syndrome: a histopathologic and immunohistochemical study. J Cutan Pathol. 2008;35(4):380–5.

    Article  PubMed  Google Scholar 

  31. Markert ML, Boeck A, Hale LP, Kloster AL, McLaughlin TM, Batchvarova MN, et al. Transplantation of thymus tissue in complete DiGeorge syndrome. N Engl J Med. 1999;341(16):1180–9.

    Article  CAS  PubMed  Google Scholar 

  32. Goldsobel AB, Haas A, Stiehm ER. Bone marrow transplantation in DiGeorge syndrome. J Pediatr. 1987;111(1):40–4.

    Article  CAS  PubMed  Google Scholar 

  33. Land MH, Garcia-Lloret MI, Borzy MS, Rao PN, Aziz N, McGhee SA, et al. Long-term results of bone marrow transplantation in complete DiGeorge syndrome. J Allergy Clin Immunol. 2007;120(4):908–15.

    Article  CAS  PubMed  Google Scholar 

  34. Janda A, Sedlacek P, Mejstrikova E, Zdrahalova K, Hrusak O, Kalina T, et al. Unrelated partially matched lymphocyte infusions in a patient with complete DiGeorge/CHARGE syndrome. Pediatr Transplant. 2007;11(4):441–7.

    Article  PubMed  Google Scholar 

  35. Markert ML, Devlin BH, Alexieff MJ, Li J, McCarthy EA, Gupton SE, et al. Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants. Blood. 2007;109(10):4539–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sullivan KE, McDonald-McGinn D, Driscoll DA, Emanuel BS, Zackai EH, Jawad AF. Longitudinal analysis of lymphocyte function and numbers in the first year of life in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Diagn Lab Immunol. 1999;6(6):906–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Piliero LM, Sanford AN, McDonald-McGinn DM, Zackai EH, Sullivan KE. T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome. Blood. 2004;103(3):1020–5.

    Article  CAS  PubMed  Google Scholar 

  38. Junker AK, Driscoll DA. Humoral immunity in DiGeorge syndrome. J Pediatr. 1995;127:231–7.

    Article  CAS  PubMed  Google Scholar 

  39. Jawad AF, Prak EL, Boyer J, McDonald-McGinn DM, 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.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McLean-Tooke A, Barge D, Spickett GP, Gennery AR. Immunologic defects in 22q11.2 deletion syndrome. J Allergy Clin Immunol. 2008;122(2):362–7.

    Article  CAS  PubMed  Google Scholar 

  42. Zemble R, Luning Prak E, McDonald K, McDonald-McGinn D, Zackai E, Sullivan K. Secondary immunologic consequences in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Clin Immunol. 2010;136(3):409–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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(5):715–23.

    Article  CAS  PubMed  Google Scholar 

  44. Tison BE, Nicholas SK, Abramson SL, Hanson IC, Paul ME, Seeborg FO, et al. Autoimmunity in a cohort of 130 pediatric patients with partial DiGeorge syndrome. J Allergy Clin Immunol. 2011;128(5):1115–7 e1-3.

    Article  PubMed  Google Scholar 

  45. Klocperk A, Grecova J, Sismova K, Kayserova J, Fronkova E, Sediva A. Helios expression in T-regulatory cells in patients with di George syndrome. J Clin Immunol. 2014;34(7):864–70.

    Article  CAS  PubMed  Google Scholar 

  46. Perez EE, Bokszczanin A, McDonald-McGinn D, Zackai EH, Sullivan KE. Safety of live viral vaccines in patients with chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Pediatrics. 2003;112(4):e325.

    Article  PubMed  Google Scholar 

  47. Moylett EH, Wasan AN, Noroski LM, Shearer WT. Live viral vaccines in patients with partial DiGeorge syndrome: clinical experience and cellular immunity. Clin Immunol. 2004;this issue.

  48. Hofstetter AM, Jakob K, Klein NP, Dekker CL, Edwards KM, Halsey NA, et al. Live vaccine use and safety in DiGeorge syndrome. Pediatrics. 2014;133(4):e946–54.

    Article  PubMed  Google Scholar 

  49. Liu AP, Chow PC, Lee PP, Mok GT, Tang WF, Lau ET, et al. Under-recognition of 22q11.2 deletion in adult Chinese patients with conotruncal anomalies: implications in transitional care. Eur J Med Genet. 2014;57(6):306–11.

    Article  PubMed  Google Scholar 

  50. Repetto GM, Guzman ML, Puga A, Calderon JF, Astete CP, Aracena M, et al. Clinical features of chromosome 22q11.2 microdeletion syndrome in 208 Chilean patients. Clin Genet. 2009;76(5):465–70.

    Article  CAS  PubMed  Google Scholar 

  51. Brown SC, Henderson BD, Buys DA, Theron M, Long MA, Smit F. Cardiac abnormalities and facial anthropometric measurements in children from the free state and northern cape provinces of South Africa with chromosome 22q11.2 microdeletion. Cardiovasc J Afr. 2010;21(1):32–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Papangeli I, Scambler P. The 22q11 deletion: DiGeorge and velocardiofacial syndromes and the role of TBX1. Wiley Interdiscip Rev Dev Biol. 2013;2(3):393–403.

    Article  CAS  PubMed  Google Scholar 

  53. Bajpai R, Chen DA, Rada-Iglesias A, Zhang J, Xiong Y, Helms J, et al. CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature. 2010;463(7283):958–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gennery AR, Slatter MA, Rice J, Hoefsloot LH, Barge D, McLean-Tooke A, et al. Mutations in CHD7 in patients with CHARGE syndrome cause T-B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome. Clin Exp Immunol. 2008;153(1):75–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. Hsu P, Ma A, Wilson M, Williams G, Curotta J, Munns CF, et al. CHARGE syndrome: a review. J Paediatr Child Health. 2014;50(7):504–11.

    Article  PubMed  Google Scholar 

  57. Hassold TJ, Jacobs PA. Trisomy in man. Annu Rev Genet. 1984;18:69–97.

    Article  CAS  PubMed  Google Scholar 

  58. Kusters MA, Verstegen RH, Gemen EF, de Vries E. Intrinsic defect of the immune system in children with Down syndrome: a review. Clin Exp Immunol. 2009;156(2):189–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Levin S, Schlesinger M, Handzel Z, Hahn T, Altman Y, Czernobilsky B, et al. Thymic deficiency in Down’s syndrome. Pediatrics. 1979;63(1):80–7.

    CAS  PubMed  Google Scholar 

  60. Larocca LM, Lauriola L, Ranelletti FO, Piantelli M, Maggiano N, Ricci R, et al. Morphological and immunohistochemical study of Down syndrome thymus. Am J Med Genet Suppl. 1990;7:225–30.

    CAS  PubMed  Google Scholar 

  61. Lima FA, Moreira-Filho CA, Ramos PL, Brentani H, Lima Lde A, Arrais M, et al. Decreased AIRE expression and global thymic hypofunction in Down syndrome. J Immunol. 2011;187(6):3422–30.

    Article  CAS  PubMed  Google Scholar 

  62. Verstegen RH, Borte S, Bok LA, van Zwieten PH, von Dobeln U, Hammarstrom L, et al. Impact of Down syndrome on the performance of neonatal screening assays for severe primary immunodeficiency diseases. J Allergy Clin Immunol. 2014;133(4):1208–11.

    Article  PubMed  Google Scholar 

  63. Costa-Carvalho BT, Martinez RM, Dias AT, Kubo CA, Barros-Nunes P, Leiva L, et al. Antibody response to pneumococcal capsular polysaccharide vaccine in Down syndrome patients. Braz J Med Biol Res. 2006;39(12):1587–92.

    Article  CAS  PubMed  Google Scholar 

  64. Gimenez-Barcons M, Casteras A, Armengol Mdel P, Porta E, Correa PA, Marin A, et al. Autoimmune predisposition in Down syndrome may result from a partial central tolerance failure due to insufficient intrathymic expression of AIRE and peripheral antigens. J Immunol. 2014;193(8):3872–9.

    Article  CAS  PubMed  Google Scholar 

  65. Pellegrini FP, Marinoni M, Frangione V, Tedeschi A, Gandini V, Ciglia F, et al. Down syndrome, autoimmunity and T regulatory cells. Clin Exp Immunol. 2012;169(3):238–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cereda A, Carey JC. The trisomy 18 syndrome. Orphanet J Rare Dis. 2012;7:81.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Van Dyke DC, Allen M. Clinical management considerations in long-term survivors with trisomy 18. Pediatrics. 1990;85(5):753–9.

    CAS  PubMed  Google Scholar 

  68. Makrydimas G, Plachouras N, Thilaganathan B, Nicolaides KH. Abnormal immunological development in fetuses with trisomy 18. Prenat Diagn. 1994;14(4):239–41.

    Article  CAS  PubMed  Google Scholar 

  69. de la Fuente MA, Recher M, Rider NL, Strauss KA, Morton DH, Adair M, et al. Reduced thymic output, cell cycle abnormalities, and increased apoptosis of T lymphocytes in patients with cartilage-hair hypoplasia. J Allergy Clin Immunol. 2011;128(1):139–46.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kavadas FD, Giliani S, Gu Y, Mazzolari E, Bates A, Pegoiani E, et al. Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations. J Allergy Clin Immunol. 2008;122(6):1178–84.

    Article  CAS  PubMed  Google Scholar 

  71. Morimoto M, Baradaran-Heravi A, Lucke T, Boerkoel CF. Schimke immunoosseous dysplasia. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA); 1993.

  72. Boerkoel CF, O’Neill S, Andre JL, Benke PJ, Bogdanovic R, Bulla M, et al. Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature. Eur J Pediatr. 2000;159(1–2):1–7.

    Article  CAS  PubMed  Google Scholar 

  73. Saraiva JM, Dinis A, Resende C, Faria E, Gomes C, Correia AJ, et al. Schimke immuno-osseous dysplasia: case report and review of 25 patients. J Med Genet. 1999;36(10):786–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Dentici ML, Di Pede A, Lepri FR, Gnazzo M, Lombardi MH, Auriti C, et al. Kabuki syndrome: clinical and molecular diagnosis in the first year of life. Arch Dis Child. 2015;100(2):158–64.

    Article  PubMed  Google Scholar 

  75. Hoffman JD, Ciprero KL, Sullivan KE, Kaplan PB, McDonald-McGinn DM, Zackai EH, et al. Immune abnormalities are a frequent manifestation of Kabuki syndrome. Am J Med Genet A. 2005;135(3):278–81.

    Article  PubMed  Google Scholar 

  76. Wessels MW, Brooks AS, Hoogeboom J, Niermeijer MF, Willems PJ. Kabuki syndrome: a review study of three hundred patients. Clin Dysmorphol. 2002;11(2):95–102.

    Article  PubMed  Google Scholar 

  77. Mattina T, Perrotta CS, Grossfeld P. Jacobsen syndrome. Orphanet J Rare Dis. 2009;4:9.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Seppanen M, Koillinen H, Mustjoki S, Tomi M, Sullivan KE. Terminal deletion of 11q with significant late-onset combined immune deficiency. J Clin Immunol. 2014;34(1):114–8.

    Article  PubMed  CAS  Google Scholar 

  79. Sirvent N, Monpoux F, Pedeutour F, Fraye M, Philip P, Ticchioni M, et al. Jacobsen’s syndrome, thrombopenia and humoral immunodeficiency. Arch Pediatr. 1998;5(12):1338–40.

    Article  CAS  PubMed  Google Scholar 

  80. Carpinelli MR, Kruse EA, Arhatari BD, Debrincat MA, Ogier JM, Bories JC, et al. Mice Haploinsufficient for Ets1 and Fli1 display middle ear abnormalities and model aspects of Jacobsen syndrome. Am J Pathol. 2015;185(7):1867–76.

    Article  CAS  PubMed  Google Scholar 

  81. Wang D, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA. Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol. 2005;17(9):1179–91.

    Article  CAS  PubMed  Google Scholar 

  82. Baskaran R, Wood LD, Whitaker LL, Canman CE, Morgan SE, Xu Y, et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature. 1997;387(6632):516–9.

    Article  CAS  PubMed  Google Scholar 

  83. Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, et al. ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet. 1998;20(4):398–400.

    Article  CAS  PubMed  Google Scholar 

  84. Wu X, Ranganathan V, Weisman DS, Heine WF, Ciccone DN, O’Neill TB, et al. ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature. 2000;405(6785):477–82.

    Article  CAS  PubMed  Google Scholar 

  85. Mallott J, Kwan A, Church J, Gonzalez-Espinosa D, Lorey F, Tang LF, et al. Newborn screening for SCID identifies patients with ataxia telangiectasia. J Clin Immunol. 2013;33(3):540–9.

    Article  CAS  PubMed  Google Scholar 

  86. Chaudhuri J, Alt FW. Class-switch recombination: interplay of transcription, DNA deamination and DNA repair. Nat Rev Immunol. 2004;4(7):541–52.

    Article  CAS  PubMed  Google Scholar 

  87. Chopra C, Davies G, Taylor M, Anderson M, Bainbridge S, Tighe P, et al. Immune deficiency in ataxia-telangiectasia: a longitudinal study of 44 patients. Clin Exp Immunol. 2014;176(2):275–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Perlman S, Becker-Catania S, Gatti RA. Ataxia-telangiectasia: diagnosis and treatment. Semin Pediatr Neurol. 2003;10(3):173–82.

    Article  PubMed  Google Scholar 

  89. Suarez F, Mahlaoui N, Canioni D, Andriamanga C, Dubois d’Enghien C, Brousse N, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol. 2015;33(2):202–8.

    Article  PubMed  Google Scholar 

  90. Chrzanowska KH, Gregorek H, Dembowska-Baginska B, Kalina MA, Digweed M. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis. 2012;7:13.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Piatosa B, van der Burg M, Siewiera K, Pac M, van Dongen JJ, 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;81(10):835–42.

    Article  PubMed  CAS  Google Scholar 

  92. Lamarche BJ, Orazio NI, Weitzman MD. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett. 2010;584(17):3682–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chrzanowska KH, Kleijer WJ, Krajewska-Walasek M, Bialecka M, Gutkowska A, Goryluk-Kozakiewicz B, et al. Eleven Polish patients with microcephaly, immunodeficiency, and chromsomal instability. Am J Med Genet. 1995;57:462–71.

    Article  CAS  PubMed  Google Scholar 

  94. Patel JP, Puck JM, Srinivasan R, Brown C, Sunderam U, Kundu K, et al. Nijmegen breakage syndrome detected by newborn screening for T cell receptor excision circles (TRECs). J Clin Immunol. 2015;35(2):227–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Digweed M, Sperling K. Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. DNA Repair (Amst). 2004;3(8–9):1207–17.

    Article  CAS  Google Scholar 

  96. van Zelm MC, Szczepanski T, van der Burg M, van Dongen JJ. Replication history of B lymphocytes reveals homeostatic proliferation and extensive antigen-induced B cell expansion. J Exp Med. 2007;204(3):645–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. van Zelm MC, van der Burg M, Langerak AW, van Dongen JJ. PID comes full circle: applications of V(D)J recombination excision circles in research, diagnostics and newborn screening of primary immunodeficiency disorders. Front Immunol. 2011;2:12.

    PubMed  PubMed Central  Google Scholar 

  98. Sottini A, Ghidini C, Zanotti C, Chiarini M, Caimi L, Lanfranchi A, et al. Simultaneous quantification of recent thymic T-cell and bone marrow B-cell emigrants in patients with primary immunodeficiency undergone to stem cell transplantation. Clin Immunol. 2010;136(2):217–27.

    Article  CAS  PubMed  Google Scholar 

  99. Kamae C, Nakagawa N, Sato H, Honma K, Mitsuiki N, Ohara O, et al. Common variable immunodeficiency classification by quantifying T-cell receptor and immunoglobulin κ-deleting recombination excision circles. J Allergy Clin Immunol. 2013;131(5):1437–40.e5.

    Article  PubMed  Google Scholar 

  100. Nakagawa N, Imai K, Kanegane H, Sato H, Yamada M, Kondoh K, et al. Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects. J Allergy Clin Immunol. 2011;128(1):223–5.e2.

    Article  CAS  PubMed  Google Scholar 

  101. Borte S, Wang N, Oskarsdóttir S, von Döbeln U, Hammarström L. Newborn screening for primary immunodeficiencies: beyond SCID and XLA. Ann N Y Acad Sci. 2011;1246:118–30.

    Article  CAS  PubMed  Google Scholar 

  102. Olbrich P, de Felipe B, Delgado-Pecellin C, Rodero R, Rojas P, Aguayo J, et al. A first pilot study on the neonatal screening of primary immunodeficiencies in Spain: TRECS and KRECS identify severe T- and B-cell lymphopenia. An Pediatr (Barc). 2014;81(5):310–7.

    Article  CAS  Google Scholar 

  103. Somech R, Lev A, Simon AJ, Korn D, Garty BZ, Amariglio N, et al. Newborn screening for severe T and B cell immunodeficiency in Israel: a pilot study. Isr Med Assoc J. 2013;15(8):404–9.

    PubMed  Google Scholar 

  104. Fleisher TA, White RM, Broder S, Nissley SP, Blaese RM, Mulvihill JJ, et al. X-linked hypogammaglobulinemia and isolated growth hormone deficiency. N Engl J Med. 1980;302(26):1429–34.

    Article  CAS  PubMed  Google Scholar 

  105. Church JA, Koch R, Shaw KN, Nye CA, Donnell GN. Immune functions in methylmalonicaciduria. J Inherit Metab Dis. 1984;7(1):12–4.

    Article  CAS  PubMed  Google Scholar 

  106. Lockitch G, Singh VK, Puterman ML, Godolphin WJ, Sheps S, Tingle AJ, et al. Age-related changes in humoral and cell-mediated immunity in Down syndrome children living at home. Pediatr Res. 1987;22(5):536–40.

    Article  CAS  PubMed  Google Scholar 

  107. Nagata M, Suzuki M, Kawamura G, Kono S, Koda N, Yamaguchi S, et al. Immunological abnormalities in a patient with lysinuric protein intolerance. Eur J Pediatr. 1987;146(4):427–8.

    Article  CAS  PubMed  Google Scholar 

  108. Wong SN, Low LC, Lau YL, Nicholls J, Chan MY. Immunodeficiency in methylmalonic acidaemia. J Paediatr Child Health. 1992;28(2):180–3.

    Article  CAS  PubMed  Google Scholar 

  109. Duriez B, Duquesnoy P, Dastot F, Bougnères P, Amselem S, Goossens M. An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency. FEBS Lett. 1994;346(2–3):165–70.

    CAS  PubMed  Google Scholar 

  110. Cossarizza A, Monti D, Montagnani G, Ortolani C, Masi M, Zannotti M, et al. Precocious aging of the immune system in Down syndrome: alteration of B lymphocytes, T-lymphocyte subsets, and cells with natural killer markers. Am J Med Genet Suppl. 1990;7:213–8.

    CAS  PubMed  Google Scholar 

  111. Ugazio AG, Maccario R, Notarangelo LD, Burgio GR. Immunology of Down syndrome: a review. Am J Med Genet Suppl. 1990;7:204–12.

    CAS  PubMed  Google Scholar 

  112. Bartsch O, Tympner KD, Schwinger E, Gorlin RJ. Mulvihill-Smith syndrome: case report and review. J Med Genet. 1994;31(9):707–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Ohashi H, Tsukahara M, Murano I, Fujita K, Matsuura S, Fukushima Y, et al. Premature aging and immunodeficiency: Mulvihill-Smith syndrome? Am J Med Genet. 1993;45(5):597–600.

    Article  CAS  PubMed  Google Scholar 

  114. Raby RB, Ward JC, Herrod HG. Propionic acidaemia and immunodeficiency. J Inherit Metab Dis. 1994;17(2):250–1.

    Article  CAS  PubMed  Google Scholar 

  115. Stewart DM, Notarangelo LD, Kurman CC, Staudt LM, Nelson DL. Molecular genetic analysis of X-linked hypogammaglobulinemia and isolated growth hormone deficiency. J Immunol. 1995;155(5):2770–4.

    CAS  PubMed  Google Scholar 

  116. Yoshida Y, Machigashira K, Suehara M, Arimura H, Moritoyo T, Nagamatsu K, et al. Immunological abnormality in patients with lysinuric protein intolerance. J Neurol Sci. 1995;134(1–2):178–82.

    Article  CAS  PubMed  Google Scholar 

  117. de Silva DC, Wheatley DN, Herriot R, Brown T, Stevenson DA, Helms P, et al. Mulvihill-Smith progeria-like syndrome: a further report with delineation of phenotype, immunologic deficits, and novel observation of fibroblast abnormalities. Am J Med Genet. 1997;69(1):56–64.

    Article  CAS  PubMed  Google Scholar 

  118. Abo K, Nishio H, Lee MJ, Tsuzuki D, Takahashi T, Yoshida S, et al. A novel single basepair insertion in exon 6 of the Bruton’s tyrosine kinase (Btk) gene from a Japanese X-linked agammaglobulinemia patient with growth hormone insufficiency. Hum Mutat. 1998;11(4):336.

    CAS  PubMed  Google Scholar 

  119. Hanley-Lopez J, Estabrooks LL, Stiehm R. Antibody deficiency in Wolf-Hirschhorn syndrome. J Pediatr. 1998;133(1):141–3.

    Article  CAS  PubMed  Google Scholar 

  120. Knight SW, Heiss NS, Vulliamy TJ, Aalfs CM, McMahon C, Richmond P, et al. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol. 1999;107(2):335–9.

    Article  CAS  PubMed  Google Scholar 

  121. Group INBSS. Nijmegen breakage syndrome. Arch Dis Child. 2000;82(5):400–6.

    Article  Google Scholar 

  122. Sznajer Y, Baumann C, David A, Journel H, Lacombe D, Perel Y, et al. Further delineation of the congenital form of X-linked dyskeratosis congenita (Hoyeraal-Hreidarsson syndrome). Eur J Pediatr. 2003;162(12):863–7.

    Article  PubMed  Google Scholar 

  123. Kranz C, Denecke J, Lehle L, Sohlbach K, Jeske S, Meinhardt F, et al. Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum Genet. 2004;74(3):545–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. de Hingh YC, van der Vossen PW, Gemen EF, Mulder AB, Hop WC, Brus F, et al. Intrinsic abnormalities of lymphocyte counts in children with down syndrome. J Pediatr. 2005;147(6):744–7.

    Article  PubMed  Google Scholar 

  125. Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C. Methylmalonic and propionic aciduria. Am J Med Genet C Semin Med Genet. 2006;142C(2):104–12.

    Article  CAS  PubMed  Google Scholar 

  126. Verstegen RH, Kusters MA, Gemen EF, DE Vries E. Down syndrome B-lymphocyte subpopulations, intrinsic defect or decreased T-lymphocyte help. Pediatr Res. 2010;67(5):563–9.

    Article  CAS  PubMed  Google Scholar 

  127. Paradowska-Stolarz AM. Wolf-Hirschhorn syndrome (WHS)—literature review on the features of the syndrome. Adv Clin Exp Med. 2014;23(3):485–9.

    Article  PubMed  Google Scholar 

  128. Sebastio G, Sperandeo MP, Andria G. Lysinuric protein intolerance: reviewing concepts on a multisystem disease. Am J Med Genet C Semin Med Genet. 2011;157C(1):54–62.

    Article  PubMed  CAS  Google Scholar 

  129. Glousker G, Touzot F, Revy P, Tzfati Y, Savage SA. Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder. Br J Haematol. 2015;170(4):457–71.

    Article  PubMed  PubMed Central  Google Scholar 

  130. MacFarland S, Hartung H. Pancytopenia in a patient with methylmalonic acidemia. Blood. 2015;125(11):1840.

    Article  CAS  PubMed  Google Scholar 

  131. Wolska-Kuśnierz B, Gregorek H, Chrzanowska K, Piątosa B, Pietrucha B, Heropolitańska-Pliszka E, et al. Nijmegen breakage syndrome: clinical and immunological features, long-term outcome and treatment options—a retrospective analysis. J Clin Immunol. 2015.

Download references

Acknowledgements

The authors would like to thank the IUIS for the inspiration for this manuscript. Dr. Puck is grateful for the support for this work from NIH RO1 AI105776; NIH Office of Rare Diseases and NIAID U54 AI082973 and R13 AI094943 to the Primary Immune Deficiency Treatment Consortium (M. Cowan, PI); the Jeffrey Modell Foundation; the Lisa and Douglas Goldman Fund; and the Michelle Platt-Ross Foundation. Dr. Sullivan is supported by the Wallace Chair of Pediatrics, USIDNET U24 AI086037 (C. Cunningham-Rundles PI), and PIDTC NIAID U54 AI082973 (M. Cowan PI).

Author information

Authors and Affiliations

  1. Division of Allergy Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Soma Jyonouchi & Kathleen E. Sullivan

  2. Division of Allergy and Immunology, Cohen Children’s Medical Center of New York, Hofstra Northwell School of Medicine, Hempstead, NY, USA

    Artemio M. Jongco

  3. Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco, and UCSF Benioff Children’s Hospital, San Francisco, CA, USA

    Jennifer Puck

Authors
  1. Soma Jyonouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Artemio M. Jongco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jennifer Puck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathleen E. Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen E. Sullivan.

Ethics declarations

Conflict of Interest

Dr. Puck’s spouse is employed at InVitae, Inc., a company that performs clinical gene sequencing. The other authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jyonouchi, S., Jongco, A.M., Puck, J. et al. Immunodeficiencies Associated with Abnormal Newborn Screening for T Cell and B Cell Lymphopenia. J Clin Immunol 37, 363–374 (2017). https://doi.org/10.1007/s10875-017-0388-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-017-0388-4

Keywords

Search

Navigation