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Internal Medicine

Severe combined immunodeficiency (SCID)

Genotypically and phenotypically heterogeneous conditions characterized by a block in T lymphocyte differentiation variably associated with abnormal development of other lymphocyte lineages (B and/or natural killer [NK] cells), leading to death early in life unless treated urgently by hematopoietic stem cell transplant.

David Vetter in his mother’s arms prior to his first walk in sterile “spacesuit” designed for him by NASA. July 29, 1977. // Photo Credit: Texas Children’s Hospital

Genotypically and phenotypically heterogeneous conditions characterized by a block in T lymphocyte differentiation variably associated with abnormal development of other lymphocyte lineages (B and/or natural killer [NK] cells), leading to death early in life unless treated urgently by hematopoietic stem cell transplant.

  • Genes involved: JAK3, RAG1, and IL-7R.

History:

Human SCID was first reported by Glanzmann and Riniker in 1950. Swiss infants with the condition were profoundly lymphopenic and died of infection before their first or second birthdays. In the ensuing years, differences were noted in inheritance patterns for SCID. This indicated that there was more than one cause for this fatal syndrome characterized by an absence of T cells and all adaptive immunity. In many families there was an X-linked recessive mode of inheritance while in others an autosomal recessive mode of inheritance was observed. The first discovered molecular cause of human SCID, adenosine deaminase deficiency, was reported in 1972. However, it was not until 21 years later, in 1993, that a second fundamental cause of the condition was found, i.e., the molecular basis of X-linked human SCID. Advances in molecular biology and the Human Genome Project as well as increased knowledge of various components of the immune system through studies of mutant mice and humans with genetically determined immunodeficiencies have all contributed to this understanding. It is now known that SCID can be caused in humans by mutations in at least 10 different genes and the likelihood is that there are other causes yet to be discovered.

Classification

Molecular classification:

  • X-lined SCID (M/C, 50-60%): Mutation in common γ-chain (γc) subunit of cytokine receptors
  • Autosomal recessive SCID:
    • M/C form: Deficiency of ADA enzyme
SCID classification | Cavazzana-Calvo, M., & Fischer, A. (2007). Gene therapy for severe combined immunodeficiency: are we there yet? The Journal of Clinical Investigation, 117(6), 1456–1465. https://doi.org/10.1172/JCI30953
Relative frequencies of the various molecular defects found in 174 consecutive cases of human SCID evaluated at Duke University Medical Center over the past 3 decades. The most common type is X-linked SCID, due to mutations in the gene encoding the common γ chain for multiple cytokine receptors; the second most common cause is adenosine deaminase deficiency (ADA def.), and the third most common cause is IL-7Rα–chain deficiency. In 25 cases the molecular defect remains unknown (those in the groups labeled autosomal recessive and unknown). No cases of CD45 deficiency have been seen at this institution. Def., deficiency. | Buckley R. H. (2004). The multiple causes of human SCID. The Journal of clinical investigation, 114(10), 1409–1411. https://doi.org/10.1172/JCI23571

Pathophysiology

41572_2015_article_bfnrdp201561_fig1_html
Lymphocyte differentiation and primary immunodeficiencies: Schematic overview of lymphocytopoiesis. Primary immunodeficiencies in the T cell lineage include severe combined immunodeficiency (SCID) and DiGeorge syndrome, although B cell malfunction is also common in SCID. | Fischer, A., Notarangelo, L. D., Neven, B., Cavazzana, M., & Puck, J. M. (2015). Severe combined immunodeficiencies and related disorders. Nature Reviews Disease Primers, 1(1), 15061. https://doi.org/10.1038/nrdp.2015.61

Clinical features

The clinical presentation is fairly uniform and is characterized by early onset of infections, mainly of the respiratory tract and gut.

Clinical presentation usually includes severe, recurrent, and potentially lethal infections early in infancy such as chronic diarrhoea, failure to thrive, lymphopenia (particularly of T lymphocytes) with profound abnormalities of cell-mediated immunity, and antibody deficiency.

x-linked-scid
The Calgary Guide | http://calgaryguide.ucalgary.ca/

Diagnosis

Newborn screening: Real-time quantitative PCR

Newborn screen for severe combined immunodeficiency uses quantitative PCR to measure the number of T-cell receptor excision circles (TREC) that are present in the blood. These are circular DNA fragments that are created as a by-product of normal T-cell development in the thymus
Pictorial explanation of T-cell receptor excision circle (TREC)–based newborn screen for severe combined immunodeficiency (SCID). The healthy infant (A) has an intact immune system; the thymus produces a normal repertoire of T cells. As unique T cells are produced, TRECs are released into the systemic circulation and can be quantified on the newborn blood spot. Despite appearing healthy externally, the infant with SCID (B) has very low or absent T-cell production. This leads to undetectable numbers of TRECs on the newborn screen, facilitating early diagnosis of SCID. | Biggs, C. M., Haddad, E., Issekutz, T. B., Roifman, C. M., & Turvey, S. E. (2017). Newborn screening for severe combined immunodeficiency: a primer for clinicians. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne, 189(50), E1551–E1557. https://doi.org/10.1503/cmaj.170561

Immunophenotype:

Presence (T–B+ SCID) or absence (T–B– SCID) of B cells & NK cells in the peripheral blood:
  • X-linked SCID: T- B+ NK-
  • Adenosine deaminase (ADA) deficiency: T- B- NK-
  • Mutations in recombination activating genes: T- B- NK+
  • IL7Rα deficiency: T- B+ NK+
rev1-2
Evaluation of patients with T- SCID. | Use Of Appropriate. (2020) Diagnostic Approach to Primary Immunodeficiency Disorders. Retrieved February 08, 2020, from https://indianpediatrics.net/june2013/june-579-586.htm

Management

Non-curative treatments:

Enzyme replacement therapy (for patients with ADA-SCID)
  • Polyethyleneglycol-coupled adenosine deaminase (PEG-ADA)
    • Metabolizes the toxic substrates of the ADA enzyme and prevents their accumulation
    • Used to restore T-cell function in the short term, enough to clear any existing infections before proceeding with curative treatment such as a bone marrow transplant

Curative treatments:

  • HSCT (Haematopoetic stem-cell transplantation)
  • Gene therapy

Summary

nrdp201564-i1
SCIDs and related disorders. (2015). Nature Reviews Disease Primers, 1, 15064. Retrieved from http://dx.doi.org/10.1038/nrdp.2015.64

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