Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Newborn screening for primary immunodeficiencies

Jennifer M Puck, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS


The goal of newborn screening (NBS) is to detect treatable disorders that are threatening to life or long-term health before they become symptomatic [1]. Early treatment of these rare disorders may significantly reduce mortality and morbidity in affected patients, making screening programs using a high-throughput, low-cost screening test with high sensitivity and specificity an important and cost-effective public health measure. Severe combined immunodeficiency (SCID) meets these criteria for inclusion in NBS due to the availability of an effective assay for T cell receptor excision circles (TRECs), a biomarker for normal T cell development. Other primary immunodeficiencies (PIDs) in addition to SCID are potential targets for NBS if suitable biomarkers can be identified and put to use in screening assays [1,2].

The rationale and tests available for NBS for PIDs are reviewed here. The general principles of NBS, screening policies, testing, and follow-up are discussed in detail separately. (See "Newborn screening".)


PIDs are a group of disorders of the immune system that result in recurrent infections, or, in some instances, predominantly dysregulated immunity, that can significantly impact long-term health and life expectancy [3]. They are estimated to occur in as many as 1 in 1200 live births [4]. Close to 300 PIDs have been described, encompassing a wide range of clinical presentations and disease severity [3]. PIDs are classified according to the immunologic mechanisms and clinical presentations that result from the underlying defects, as well as the functional consequences of mutations upon their gene products. Adaptive immune defects predominantly affect antigen-driven processes. These defects include humoral immune deficiencies (due to impaired production of antibody by B cells) and combined immunodeficiencies (with impairments in both T and B cells). Innate immune disorders arise from impaired antigen-independent pathways and include defects in natural killer (NK) cell cytotoxicity, toll-like receptor (TLR) activation, phagocytosis, macrophage activation, and complement defects. More and more PIDs are associated with single gene defects. (See "Severe combined immunodeficiency (SCID): An overview" and "Combined immunodeficiencies", section on 'Overview' and "Primary humoral immunodeficiencies: An overview" and "Primary disorders of phagocytic function: An overview" and "Inherited disorders of the complement system" and "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

Treatment for PIDs depends upon the part(s) of the immune system affected and can include hematopoietic cell transplantation (HCT), immune globulin replacement therapy, and antimicrobial therapy to prevent or limit infections. Delay in diagnosis and treatment of PIDs leads to significant morbidity and sometimes early death from recurrent infections. Thus, early identification via newborn screening (NBS) should decrease the morbidity and mortality associated with these disorders. A retrospective study of 240 infants diagnosed with severe combined immunodeficiency (SCID) showed that overall survival (OS) at five years after transplant was similar amongst infants who received HCT at age <3.5 months (94 percent OS, 95% CI 85-98), at age >3.5 months while continuously infection free (90 percent OS, 95% CI 67-98), and even at age >3.5 months provided all infections had been treated and resolved prior to HCT (82 percent OS, 95% CI 70-90). In contrast, infants who were older than 3.5 months with active infection at time of transplant had greatly reduced OS (50 percent OS, 95% CI 39-61) [5]. These data further support the importance of NBS for SCID to allow early detection prior to the onset of infections. (See "Hematopoietic cell transplantation for primary immunodeficiency" and "Primary immunodeficiency: Overview of management" and "Immune globulin therapy in primary immunodeficiency" and "Gene therapy for primary immunodeficiency".)


The first group of PIDs targeted for newborn screening (NBS) was severe combined immunodeficiency (SCID). The term "SCID" encompasses a genetically heterogenous group of disorders characterized by profound impairment in T cell development and function with either primary or secondary defects in B cells (table 1). Infants with SCID are generally healthy at birth, protected by transplacentally acquired maternal immunoglobulin G (IgG) antibodies in the first few months of life. As this protection wanes, these infants develop severe and recurrent infections (including infections caused by live-virus vaccines given early in life), chronic diarrhea, and poor weight gain. Hematopoietic cell transplantation (HCT) has been shown to be an effective treatment for SCID, particularly if performed early in infancy, before the development of recurrent and increasingly severe infections. Infants with SCID without reconstitution of a functioning immune system usually die of overwhelming infection by one year of age. Only approximately 20 percent of infants with SCID have a family history that prompts early testing [6]. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations' and "Hematopoietic cell transplantation for primary immunodeficiency", section on 'Early identification'.)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jan 2017. | This topic last updated: Wed Jan 04 00:00:00 GMT 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Wilson JM, Jungner YG. [Principles and practice of mass screening for disease]. Bol Oficina Sanit Panam 1968; 65:281.
  2. Borte S, von Döbeln U, Hammarström L. Guidelines for newborn screening of primary immunodeficiency diseases. Curr Opin Hematol 2013; 20:48.
  3. Picard C, Al-Herz W, Bousfiha A, 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; 35:696.
  4. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol 2007; 27:497.
  5. Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 2014; 371:434.
  6. Puck JM, Middelton L, Pepper AE. Carrier and prenatal diagnosis of X-linked severe combined immunodeficiency: mutation detection methods and utilization. Hum Genet 1997; 99:628.
  7. Moore EC, Meuwissen HJ. Screening for ADA deficiency. J Pediatr 1974; 85:802.
  8. Hirschhorn R. Adenosine deaminase deficiency. Immunodefic Rev 1990; 2:175.
  9. Kalman L, Lindegren ML, Kobrynski L, et al. Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. Genet Med 2004; 6:16.
  10. Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol 2005; 115:391.
  11. Morinishi Y, Imai K, Nakagawa N, et al. Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards. J Pediatr 2009; 155:829.
  12. 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; 129:607.
  13. Accetta D, Syverson G, Bonacci B, 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; 127:535.
  14. Cossu F. Genetics of SCID. Ital J Pediatr 2010; 36:76.
  15. Goldenberg AJ, Sharp RR. The ethical hazards and programmatic challenges of genomic newborn screening. JAMA 2012; 307:461.
  16. Dondorp WJ, de Wert GM, Niermeijer MF. Genomic sequencing in newborn screening programs. JAMA 2012; 307:2146; author reply 2147.
  17. Hazenberg MD, Otto SA, Cohen Stuart JW, et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med 2000; 6:1036.
  18. Douek DC, McFarland RD, Keiser PH, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998; 396:690.
  19. Kwan A, Church JA, Cowan MJ, 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; 132:140.
  20. Kwan A, Abraham RS, Currier R, et al. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA 2014; 312:729.
  21. Verbsky JW, Baker MW, Grossman WJ, et al. Newborn screening for severe combined immunodeficiency; the Wisconsin experience (2008-2011). J Clin Immunol 2012; 32:82.
  22. Gerstel-Thompson JL, Wilkey JF, Baptiste JC, et al. High-throughput multiplexed T-cell-receptor excision circle quantitative PCR assay with internal controls for detection of severe combined immunodeficiency in population-based newborn screening. Clin Chem 2010; 56:1466.
  23. Vogel BH, Bonagura V, Weinberg GA, et al. Newborn screening for SCID in New York State: experience from the first two years. J Clin Immunol 2014; 34:289.
  24. Adams SP, Rashid S, Premachandra T, et al. Screening of neonatal UK dried blood spots using a duplex TREC screening assay. J Clin Immunol 2014; 34:323.
  25. Audrain M, Thomas C, Mirallie S, et al. Evaluation of the T-cell receptor excision circle assay performances for severe combined immunodeficiency neonatal screening on Guthrie cards in a French single centre study. Clin Immunol 2014; 150:137.
  26. Somech R, Lev A, Simon AJ, et al. Newborn screening for severe T and B cell immunodeficiency in Israel: a pilot study. Isr Med Assoc J 2013; 15:404.
  27. Chien YH, Chiang SC, Chang KL, et al. Incidence of severe combined immunodeficiency through newborn screening in a Chinese population. J Formos Med Assoc 2015; 114:12.
  28. Dasouki M, Okonkwo KC, Ray A, et al. Deficient T Cell Receptor Excision Circles (TRECs) in autosomal recessive hyper IgE syndrome caused by DOCK8 mutation: implications for pathogenesis and potential detection by newborn screening. Clin Immunol 2011; 141:128.
  29. Mallott J, Kwan A, Church J, et al. Newborn screening for SCID identifies patients with ataxia telangiectasia. J Clin Immunol 2013; 33:540.
  30. Grazioli S, Bennett M, Hildebrand KJ, et al. Limitation of TREC-based newborn screening for ZAP70 Severe Combined Immunodeficiency. Clin Immunol 2014; 153:209.
  31. Kuo CY, Chase J, Garcia Lloret M, et al. Newborn screening for severe combined immunodeficiency does not identify bare lymphocyte syndrome. J Allergy Clin Immunol 2013; 131:1693.
  32. Lev A, Simon AJ, Bareket M, et al. The kinetics of early T and B cell immune recovery after bone marrow transplantation in RAG-2-deficient SCID patients. PLoS One 2012; 7:e30494.
  33. Sottini A, Ghidini C, Zanotti C, 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; 136:217.
  34. Nakagawa N, Imai K, Kanegane H, 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; 128:223.
  35. Borte S, von Döbeln U, Fasth A, et al. Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood 2012; 119:2552.