Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID), also called “bubble boy disease,” is a rare genetic disorder in which the development of functional B and T cells is disturbed due to several genetic mutations that result in reduced or absent immune function. It is the most severe form of primary immunodeficiency and is characterized by dysfunction in both humoral and cell-mediated immune responses. Multiple mutations can result in heterogeneous types of SCID. Patients present with severe and recurrent infections within the first months of life. Management includes IV immunoglobulins and bone marrow transplantation. If left untreated, SCID is usually fatal within the 1st year of life.

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Epidemiology and Etiology

Epidemiology

  • Prevalence: < 1 in 100,000 live births
  • Higher prevalence rates are found in areas and cultures in which consanguineous mating is common.
  • Incidence of 1 in 2,500 among Navajo and Apache children

Etiology

At least 12 genes are known to cause severe combined immunodeficiency (SCID) if mutated, including those that encode for the following:

  • The common γ chain shared by the receptors for the cytokines IL-2, IL-4, IL-7, IL-9, and IL-15
    • IL-7 is the most important cytokine because it stimulates the survival and expansion of immature B- and T-cell precursors. 
  • Adenosine deaminase (ADA)
  • Purine nucleoside phosphorylase
  • Mitochondrial adenylate kinase 2
  • Janus kinase-3 (JAK3)
  • RAG-1 and RAG-2 genes

The pattern of inheritance depends on the type of genetic mutation involved:

  • Approximately 50% of cases follow an X-linked recessive pattern of inheritance and are associated with mutations of the common γ chain.
  • Approximately 40%50% of cases follow an autosomal recessive pattern of inheritance and are often (50%) associated with mutations of ADA.

Pathophysiology

  • The gene affected will determine which type of cell is lacking or deficient, with T cells, B cells, and NK cells being the most commonly affected. 
  • All types of SCID are categorized by a low or absent level of T cells.
  • Receptors containing the common γ chain are located on the surface of immature cells in bone marrow, which assist in forming lymphocytes; regulate the growth and maturation of several subtypes of T cells, B cells, and natural killer cells; and regulate the entire immune system.
  • Mutations affecting these receptors lead to atrophic or hypoplastic lymphoid organs and lymphopenia.
  • Thus, patients with SCID have extreme susceptibility to infection in infancy.
Table: Possible SCID phenotypes
PhenotypeGenetic defect
TB+NKγC, JAK3
TBNK+RAG-1, RAG-2, Artemis, DNA ligase IV, Cernunnos, DNA PKcs
TB+NK+IL-7Rα, CD3δ, CD3ζ, Coronin-1A, ZAP-7O, CD45
TBNKADA, AK2
Table: Types of SCID
SyndromeDefect
X-linked severe combined immunodeficiencyMutations in the gene encoding the common γ chain, a protein that is shared by the receptors for interleukins IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21
Adenosine deaminase deficiency
  • Caused by a defective enzyme, ADA, which is necessary for the breakdown of purines
  • Leads to an accumulation of dATP, which inhibits the activity of ribonucleotide reductase (enzyme that generates deoxyribonucleotides)
Purine nucleoside phosphorylase (PNP) deficiencyAutosomal recessive disorder involving mutations of the PNP gene
Reticular dysgenesisInability of granulocyte precursors to form granules secondary to mitochondrial adenylate kinase 2 malfunction
Omenn syndrome
  • Caused by a partial loss of RAG gene function
  • Leads to loss or defective gene recombination in T- and B-cell receptors, which results in impaired pathogen recognition
Bare lymphocyte syndrome
  • Autosomal recessive condition in which MHC molecules are affected
  • This type is notable for having normal levels of B and T cells; their functionality is impaired, not their development.
JAK3JAK3 is an enzyme that mediates transduction downstream of the γc signals.

Clinical Presentation

The disease typically presents in early childhood (26 months). Severe and recurrent opportunistic infections are seen in affected individuals.

  • Chronic diarrhea
  • Dermatitis
  • Failure to thrive due to recurrent infections and malnutrition
  • Viral infections (e.g., cytomegalovirus [CMV] rotavirus, varicella)
  • Meningitis
  • Candidiasis
  • Mycobacterium avium complex (MAC) infection
  • Pneumocystis pneumonia (common presentation in patients with no T cells)
  • Lymph nodes, thymus, and tonsils are usually hypoplastic or absent in these patients.

Diagnosis

  • Early diagnosis is possible through newborn screening for SCID.
    • Although screening is not available or used globally, all newborns in the United States are screened for SCID. 
    • Without newborn screening, diagnosis is difficult and worsens prognosis.
    • The SCID newborn screening test measures T-cell receptor excision circles (TRECs), a byproduct of T-cell development. A lack of TRECs confirms SCID. 
  • Symptoms that create suspicion of or support the diagnosis of SCID: 
    • Family history of infant deaths
    • Presence of a chronic cough
    • Presence of hyperinflated lungs
    • Recurrent and persistent infections 
  • To confirm the diagnosis:
    • Complete blood count: reduced levels of T cells and B cells or NK cells (or both)
    • Flow cytometry: T-cell subpopulation deficiency (definitive diagnosis)
  • Ancillary tests in SCID patients (if needed):
    • Chest X-ray: absence of thymus
    • Lymph node biopsy: absence of germinal centers
SCID X-ray

Chest X-ray of a 5-month-old boy with SCID complicated by disseminated bacillus Calmette-Guérin (BCG) disease showing the absence of a thymus and bilateral areas of opacities

Image: “Chest X-ray” by Pediatric Intensive Care Unit, Hospital Dona Estefânia, 1169-045 Lisboa, Portugal. License: CC BY 3.0

Management and Prognosis

  • Bone marrow transplantation before 3 months of age
    • Avoid public exposure prior to transplant.
    • The best donor is ideally a sibling with a close tissue match.
  • Intravenous immunoglobulin (IVIG) infusion
    • Replaces missing immunoglobulin from B-cell dysfunction due to missing T cells
    • The results of IVIG last approximately 3 weeks.
  • Pneumocystis pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole (TMP/SMX) starting at 1 month of age
  • Reverse isolation
  • Enzyme replacement for ADA deficiency
  • Investigational therapies include gene therapy.
    • SCID is the first disease in which gene therapy has successfully replaced the mutated gene.
    • Still considered experimental or investigational because some of the patients who received the treatment later developed leukemia
  • Prognosis:
    • Highly fatal
    • Death results from repeated infections before the age of 2

Differential Diagnosis

The following conditions are differential diagnoses for SCID:

  • DiGeorge syndrome: a condition caused by a microdeletion at a location designated q11.2 of chromosome 22, due to defective development of the 3rd and 4th pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). Other manifestations include characteristic facial features, congenital heart defects, frequent infections, and neuropsychiatric disorders.
  • CHARGE syndrome: a rare genetic disorder in children affecting almost all body systems due to impaired gene expression as a result of inherited mutations in the specific genes. CHARGE stands for Coloboma, Heart defects, Atresia choanae, Growth retardation, Genital abnormalities, and Ear abnormalities. The syndrome is usually associated with hypoplasia or aplasia of the thymus, leading to immunodeficiency.
  • Wiskott-Aldrich syndrome: an X-linked mixed disorder of B- and T-cell deficiency. Wiskott-Aldrich syndrome is caused by a WAS gene mutation that leads to impaired actin cytoskeleton, phagocytosis and chemotaxis, impaired platelet development, and, in general, a loss of humoral and cellular responses. The syndrome presents as eczema, bleeding disorders, recurrent opportunistic infections, and autoimmunity.
  • HIV infection and AIDS: caused by a single-stranded RNA virus in the Retroviridae family; transmitted through the exchange of body fluids such as semen and blood. Presentation is marked by a deterioration of the immune system, beginning with constitutional symptoms such as lymphadenopathy, and advancing into AIDS-defining illnesses, such as opportunistic infections.
  • Common variable immunodeficiency (CVID): a type of primary immunodeficiency characterized by reduced serum levels of immunoglobulins G, A, and M. The underlying causes are unknown. Patients with this condition are prone to infections in the gastrointestinal tract and the upper and lower respiratory tracts and have a higher risk of developing autoimmune, granulomatous, and neoplastic diseases.

References

  1. National Institute of Allergy and Infectious Diseases (2019. https://www.niaid.nih.gov/diseases-conditions/severe-combined-immunodeficiency-scid
  2. American Academy of Asthma Allergy & Immunology. Retrieved August 28, 2020, from https://www.aaaai.org/conditions-and-treatments/primary-immunodeficiency-disease/severe-combined-immunodeficiency#:~:text=Severe%20Combined%20Immunodeficiency%20(SCID)%20is,be%20the%20most%20serious%20PIDD.
  3. Le, T., & Bhushan, V. (2020). First Aid for the USMLE Step 1 (30th anniversary edition) P. 117. New York: McGraw-Hill Medical.
  4. Kumar, V., Abbas, A. K., Aster, J. C., & Robbins, S. L. (2013). Robbins basic pathology, p. 142. Philadelphia, PA: Elsevier/Saunders.

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