Severe Combined Immunodeficiency


  • Severe combined immunodeficiency (SCID) is a congenital immunodeficiency  caused by a collection of genetic mutations that lead to T cell, B cell, and NK cell dysfunction.
  • SCID patients lack lymphoid tissue, and absence of a thymic shadow on chest X-ray is a typical finding.
  • The incidence of SCID is 1 case per 40,000 to 100,000 live births.


  • Genes mutated in SCID are involved in:
    • Cytokine signaling
    • Antigen presentation
    • VDJ recombination
    • T cell receptor (TCR) signaling
    • Basic cellular functions.
  • About 50% of cases are X-linked
  • The most common defect is a mutation in IL2RG
    • Encodes the gamma chain of a cytokine receptor shared by multiple cytokines required for lymphocyte development.
  • Another common cause of SCID is a mutation in adenosine deaminase, (ADA), which encodes an adenosine deaminase required for detoxification and excretion of cytotoxic metabolites that accumulate in rapidly dividing cells.
  • While many mutations have been characterized, the genetic defect is unknown in 14% of SCID cases.


Clinical Findings

  • If untreated, children born with SCID experience:
    • Recurrent, severe infections including:
      • Chronic viral diarrhea
      • Mucocutaneous candidiasis
      • Pneumonias secondary to:
        • Pneumocystis jirovecii
        • Adenovirus
        • CMV
    • Failure to thrive and death typically in the first year of life.
    • Susceptibilityto graft-versus-host-disease (GVHD):
      • After transfusion of blood products containing viable T cells
      • From transplacental transfer of maternal T cells
    • Elevated cancer risk
      • 1.5% of SCID patients develop cancer at the median age of 1.6 years.
      • The most common malignancy is non-Hodgkin lymphoma.

Common Laboratory Abnormalities

  • Low absolute lymphocyte count (<2500 cells/µL)
  • Low lymphocyte subpopulations
  • Absent to low T cell mitogen repsonse
  • Hypogammaglobulinemia
    • Very low serum IgM, IgA, and IgE

Diagnosis should be suspected in the following clinical scenarios:

  • Unexplained lymphopenia
  • Recurrent fevers
  • Failure to thrive
  • Recurrence of sever episodes of:
    • Oral thrush
    • Mouth ulcers
    • Respiratory syncytial virus
    • Rerpes simplex virus
    • Varicella zoster virus
    • Influenza
    • Measles
  • Adverse reactions caused by live vaccines (e.g. rotavirus, varicella)
  • A family history of SCID

Differential Diagnosis

  • Extreme malnutrition
  • HIV
  • Intestinal lymphangiectasia
  • Other combined immunodeficiency syndromes (e.g. Wiskott-Aldrich Syndrome, DiGeorge Syndrome)


Screening for SCID

In 2010, SCID was added to the Recommended Uniform Screening Panel for the newborn screen.

  • The screening test relies a byproduct of T-cell maturation to detect low numbers of naive T-cells, a hallmark of SCID.
  • During VDJ rearrangement, the process used to generate diverse TCRs, small loops of DNA called T-cell receptor excision circles (TRECs) are excised from genomic DNA.
    • As they are no longer part of the genome, TRECs do not replicate and are detectable only in naive T cells.
  • In the newborn screen, quantitative real time (qRT)-PCR is used to quantify the TRECs and thus the number of naive T cells present in a blood sample.
  • A control for DNA integrity can be done through qRT-PCR of a housekeeping gene.
  • The false positive rate and specificity of this screening test are 0.018% and 99.98%, respectively.
  • To date, there have been no known false negative tests, but there are causes of SCID, such as late onset ADA, that would result in a false negative.
  • If the screening test is positive, Illinois recommends referral to a designated pediatric immunologist for diagnostic flow cytometry.


The definitive treatment for SCID is hematopoietic stem cell transplantation (HSCT).

  • Until transplantation, care centers around prevention of infections. It is recommended that SCID patients receive IVIG, prophylaxis for P. jirovecii, and Palivizumab.
  • Live vaccines should be withheld and all blood products given should be irradiated, leuko-depleted and CMV negative.
  • In addition to HSCT, alternative forms of treatment are available for some forms of SCID.
    • Enzyme replacement therapy (PEG-ADA) is available for SCID due to ADA deficiency and is used for patients who do not have a haploidentical donor.
      • PEG-ADA can be given as a once or twice weekly intramuscular injection and immune reconstitution is achieved after several years, with most patients able to discontinued IVIG treatment after 3-7 year.
    • Gene therapy is now being developed for SCID secondary to ADA and IL2RG mutations and has been used with success in a small number of patients








  1. Bonilla, FA. Severe combined immunodeficiency (SCID): An overview. In: UpToDate, TePas E (Ed), UpToDate, Waltham, MA. (Accessed on August 8, 2015)
  2. Bonilla, FA. Gene therapy for primary immunodeficiency. In: UpToDate, TePas E (Ed), UpToDate, Waltham, MA. (Accessed on August 8, 2015)
  3. Illinois Department of Public Health. Severe Combined Immune Deficiency Information for Physicians and Other Health Care Professionals. (Accessed on August 8, 2015)
  4. Rubinstein, A. Adenosine deaminase deficiency: Treatment. In: UpToDate, TePas E (Ed), UpToDate, Waltham, MA. (Accessed on August 8, 2015)
  5. Verbsky, J and Routes, J. Screening for and Treatments of Congenital Immunodeficiency Diseases. Clinics in Perinatology 2014; 41, 4.


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