Genetics

Severe Combined Immunodeficiency

Introduction

  • 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.

Pathology

  • 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.

Treatment         

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

 

 

Resources

 

 

 

References

  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. http://www.idph.state.il.us/HealthWellness/fs/scid.htm (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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