Combined immunodeficiencies are characterized by impaired numbers and function of T- and B-cells(1). In its most severe form it leads to a Severe combined immunodeficiency (SCID) (1-5). SCID describes a heterogeneous group of genetic defects, all of which lead to profoundly impaired differentiation of T lymphocytes and (in some cases) additional blocks in the differentiation of B lymphocytes and/or natural killer (NK) lymphocytes. These defects result in low levels of lymphocytes as well as immunoglobulins , with inability to fight infection and early death unless treated promptly. The majority of SCID patients have a mutation in genes coding for the common cytokine receptor known as the common gamma chain(6,7). SCID patients usually present in the first few months of life with respiratory (e.g. pneumonia) or gastro-intestinal infections (e.g. gastroenteritis) and a failure to thrive. SCID patients have also increased tendency for opportunistic infections defined as infections that are more frequent or more severe because of immunosuppression (e.g. Pneumocystis pneumonia, cytomegalovirus infection, candidiasis, and tuberculosis ) (8).

Less severe functional impairments may result in defect preventing lymphocyte maturation and presenting clinically as Omenn's syndrome (OS). Unlike typical SCID, patients with OS have enlarged lymphoid tissue (lymph nodes , spleen), severe rash, increased IgE levels, and increased levels of eosinophils(2).

SCID patients should be treated supportively with antibacterial and antifungal prophylactic drugs and with immunoglobulin replacement therapy. Early hematopoietic stem cell transplantation from a related donor is a life-saving and life-sustaining treatment for patients with any type of SCID, even in the absence of HLA-identical donor(9). The source of the stem cells used for the transplantation may be either the bone marrow or umbilical cord blood (UCB) (10). Recent studies suggest overall impressive efficacy of gene therapy for several forms of SCID(7).

Recent evidence indicates the benefits of early treatment of SCID through detection of, the T cell receptor excision circle (TREC). TREC reflect T cell development. Abnormal TREC levels serve as a SCID marker. TREC levels can be measured in the newborn dried blood spot and has recently been recommended for inclusion in the US uniform panel of newborn screening conditions (11,12).

1. Niehues T, Perez-Becker R, Schuetz C. More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol 2010;135:183-192.

2. Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol 2008;122:1082-1086.

3. Pike-Overzet K, van der BM, Wagemaker G, van Dongen JJ, Staal FJ. New insights and unresolved issues regarding insertional mutagenesis in X-linked SCID gene therapy. Mol Ther 2007;15:1910-1916.

4. Grunebaum E, Sharfe N, Roifman CM. Human T cell immunodeficiency: when signal transduction goes wrong. Immunol Res 2006;35:117-126.

5. Fischer A, Le Deist F, Hacein-Bey-Abina S, Andre-Schmutz I, Basile GS, de Villartay JP et al. Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunol Rev 2005;203:98-109.

6. Cole TS, Cant AJ. Clinical experience in T cell deficient patients. Allergy Asthma Clin Immunol 2010;6:9.

7. Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. 20 years of gene therapy for SCID. Nat Immunol 2010;11:457-460.

8. Kaplan JE, Benson C, Holmes KH, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58:1-207.

9. Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 1999;340:508-516.

10. Knutsen AP, Wall DA. Umbilical cord blood transplantation in severe T-cell immunodeficiency disorders: two-year experience. J Clin Immunol 2000;20:466-476.

11. Lipstein EA, Vorono S, Browning MF, Green NS, Kemper AR, Knapp AA et al. Systematic evidence review of newborn screening and treatment of severe combined immunodeficiency. Pediatrics 2010;125:e1226-e1235.

12. 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.