eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

Severe Combined Immunodeficiency

Author: Elizabeth A Secord, MD, Clinical Associate Professor, Department of Pediatrics, Division of Pediatric Immunology, Wayne State University
Coauthor(s): Eyal Oren, MD, Consulting Staff, Institute for Asthma and Allergy
Contributor Information and Disclosures

Updated: May 5, 2009

Introduction

Background

Severe combined immunodeficiency (SCID) is a disorder that results from any of a heterogenous group of genetic conditions affecting the immune system. SCID leads to severe T- and B-cell dysfunction. Without intervention, the T- and B-cell dysfunction usually results in severe infection and death in children by age 2 years.

The most common genetic condition responsible for SCID is a mutation of the common gamma chain of the interleukin (IL) receptors shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (T-cell^-, natural killer [NK] cell^-, B-cell⁺).¹ This protein is encoded on the X chromosome; therefore, this variant of SCID is X-linked (and is sometimes referred to as X-linked SCID). These patients account for approximately 50% of all patients with SCID.

Autosomal recessive SCID (formerly known as Swiss-type agammaglobulinemia) includes Janus-associated kinase 3 (JAK3; T^-, NK^-, B⁺) deficiency,^2,3,4,5 adenosine deaminase (ADA) deficiency (T^-, B^-, NK^+/-),⁶ bare lymphocyte syndrome (a somewhat milder SCID),^7,8,9 zeta chain–associated protein (ZAP)-70 deficiency,¹⁰ reticular dysgenesis, IL-7 receptor α deficiency, recombination-activating gene (RAG)-1 and RAG-2 deficiency (T^-, B^-, NK⁺),¹¹ ligase 4 deficiency (T^-, B^-, NK⁺),¹² and CD45 deficiency.¹³

Several deficiencies of the CD3 complex (CD3 γ, ε, δ, and ζ) are associated with SCID.^14,15 Omenn syndrome is associated with Artemis defect.¹⁶ Purinenucleotide phosphorylase (PNP) deficiency and IL-2 deficiency are severe enough in nature to be classified as SCID, and other defects are identified every year.¹⁷

These are the most common and best characterized forms of SCID, but not all of the genetic conditions leading to SCID are well characterized. Infants with SCID usually present with infections that are secondary to the lack of T-cell function (eg, Pneumocystis jiroveci pneumonia [PCP], systemic candidiasis, generalized herpetic infections, severe failure to thrive secondary to gut infections/diarrhea). Graft versus host disease (GVHD) from nonirradiated blood products is an important cause of morbidity. SCID is considered a pediatric emergency and requires prompt workup and treatment.

Pathophysiology

The pathophysiology and molecular biology vary; however, the lack of T-cell and B-cell function is the common endpoint in all forms of SCID.

Cellular hallmarks that help differentiate between various forms of SCID are as follow:

• X-linked SCID: Lymphopenia occurs primarily from the absence or near absence of T cells (CD3⁺) and natural killer (NK) cells. Variable levels of B cells occur, which do not make functional antibodies.
• JAK3 deficiency: Lymphopenia occurs primarily from the absence or near absence of T cells (CD3⁺) and NK cells. Normal or high levels of B cells occur, which do not make functional antibodies.
• ADA deficiency: Lymphopenia occurs from the death of T and B cells secondary to the accumulation of toxic metabolites in the purine salvage pathway. Functional antibodies are decreased or absent.
• ZAP-70 deficiency: Lymphopenia occurs because of the absence of CD8⁺ T cells. As in all types of SCID, no antibody formation is present.
• Reticular dysgenesis: Lymphopenia occurs from the absence of myeloid cells in the bone marrow. Red blood cells and platelets are present and functioning.
• Omenn syndrome: Normal or elevated T-cell numbers are present, but these are of maternal, not fetal, origin. The B cells are usually undetectable, NK cells are present, and the total immunoglobulin level is markedly low with poor antibody production. Eosinophils are elevated, and the total serum immunoglobulin E (IgE) level is elevated.

Combined immune deficiencies that are sometimes severe enough to be classified as SCID are as follow:

• PNP deficiency: Lymphopenia occurs from the death of T cells secondary to the accumulation of toxic metabolites in the purine salvage pathway. This deficiency differs from ADA deficiency because circulating B cells are normal in number. However, B-cell function is poor, as evidenced by the lack of antibody formation. PNP deficiency can be severe enough to be classified as SCID.
• Bare lymphocyte syndrome: The lymphocyte count is normal or mildly reduced, the CD4⁺ T cells are decreased, and the CD8⁺ T cell numbers are normal or mildly increased. The B-cell numbers are normal or mildly decreased, but the ability to make antibodies is decreased. Bare lymphocyte syndrome is sometimes classified as SCID.
• IL-2 deficiency: Normal, or near normal, numbers of T cells exist (both CD4⁺ and CD8⁺). The T cells fail to proliferate in vitro when stimulated with mitogens, unless IL-2 is added to the culture medium. The production of functional antibody is decreased. IL-2 deficiency may be severe enough to be classified as SCID.

Molecular abnormalities in various forms of SCID are as follow:

• X-linked SCID: Mutation of the common gamma chain (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, IL-21R) of the IL receptors occurs, resulting in loss of cytokine function. Loss of IL-2R function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of IL-15R function leads to the ablation of NK cell development.^1,2,3
• JAK3 deficiency: JAK3 is a protein tyrosine kinase (PTK) that associates with the common gamma chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of X-linked SCID.^4,5
• IL-2 production deficiency: The exact molecular defect is unknown, but it is often associated with other cytokine production defects.
• Bare lymphocyte syndrome: This is a deficiency of major histocompatibility complex (MHC). MHC type II is decreased on mononuclear cells. MHC type I levels may be decreased, or MHC type I may be absent. The defect occurs in a gene regulating expression of MHC type II.^7,8
• ZAP-70 deficiency: A mutation occurs in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus. A selection absence of CD8+ T cells and an abundance of nonfunctioning CD4+ T cells occurs. ZAP-70 is apparently needed in the selection of CD8+ T cells and is necessary for T cell functioning, thus the nonfunctioning CD4+ cells.¹⁰
• Omenn syndrome: Mutations that impair the function of immunoglobulin and TCR recombinase genes (ie, RAG1, RAG2 genes) are responsible for this syndrome. These include the Artemis mutation (enzyme that opens DNA hairpin during variable diversity joining [VDJ] rearrangement) and RAG1 and RAG2 deficiencies.^11,16
• ADA deficiency: ADA is an enzyme that breaks down purines. When it is absent, deoxyadenosine triphosphate (dATP) builds up and inhibits the enzymes necessary for lymphocyte proliferation. It causes B-, T-, and NK-cell deficiency.⁶

Frequency

United States

SCID occurs in approximately 1 in 50,000-75,000 live births. The incidence was previously reported at approximately 1 in 100,000, but improved early identification of affected subjects revealed that the true incidence is higher than previously believed. Approximately 50% of all SCID cases are X-linked (ie, mutation of the common gamma chain). The remaining 50% are various forms of autosomal recessive SCID. Approximately 25% of the patients with an autosomal recessive SCID are JAK3 deficient, and 40% are ADA deficient. The other disorders make up the remaining 35% of autosomal recessive patients.

International

International frequency is similar to that of the United States. X-linked SCID, like other X-linked disorders, has a higher frequency in populations with increased consanguinity.

Mortality/Morbidity

Without treatment, death from infection usually occurs within the first 2 years of life. GVHD from maternal cell engraftment can occur in any SCID case. The transfusion of nonirradiated blood products is an important cause of GVHD in all forms of SCID.

Race

No racial predisposition exists for most forms of SCID, but most patients with ZAP-70 deficiency and CD3 δ are Mennonites. The Artemis gene deficiency is seen predominately in Navajo and Apache Native Americans.

Sex

Approximately 50% of SCID cases are X-linked (ie, occurring only in males). No sexual predisposition is associated with autosomal recessive SCID.

Age

The average age at the onset of symptoms is 2 months.

Clinical

History

• Family history of consanguinity
• Sibling death in infancy and/or previous miscarriages in mother
• Family history of severe combined immunodeficiency (SCID)
• Poor feeding and poor weight gain
• Chronic diarrhea
• Previous infections, especially pneumonia

Physical

Abnormal physical findings are primarily due to infection or graft versus host disease (GVHD) and are not directly due to the primary immunodeficiency. The patient may present with the following:

• Failure to thrive, manifesting as decreased weight, height, and head circumference
• Dehydration from chronic diarrhea
• Eczematous rash from GVHD, which may be mistaken for atopic dermatitis, especially in Omenn syndrome
• Increased respiratory rate and effort and crepitations secondary to pneumonia (especially Pneumocystis jiroveci pneumonia)
• Fever from sepsis, systemic fungal infections, or generalized herpes
• Absent lymphatic tissue, including tonsils
• Lymphadenopathy and hepatosplenomegaly in Omenn syndrome or bare lymphocyte syndrome
• Neurological sequelae and developmental regression (loss of developmental milestones), especially in purinenucleotide phosphorylase (PNP) deficiency (the cause of which is genetic, not infectious)
• Candidiasis

Causes

• Genetic (molecular defects)
  • X-linked SCID: Mutation of the common gamma chain shared by multiple interleukin receptors (ie, IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, IL-21R) occurs, resulting in loss of cytokine function. Loss of IL-2R function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of IL-15R function leads to the ablation of natural killer (NK) cell development. IL-21 is key in the proliferation and differentiation of T, B, and NK cells. The ligand binding of this receptor leads to the activation of Janus-associated kinase (JAK)1, JAK3, STAT1, and STAT3.
  • JAK3 deficiency: JAK3 is a protein tyrosine kinase (PTK) that associates with the common gamma chain shared by the multiple receptors listed above. This deficiency has the same clinical manifestations as those of X-linked SCID.
  • Adenosine deaminase (ADA) and PNP deficiencies: These are associated with enzyme deficiencies in the purine salvage pathway; toxic metabolites are responsible for the destruction of lymphocytes that cause the immune deficiency.
  • Bare lymphocyte syndrome: This is associated with a molecular defect in the gene regulating major histocompatibility (MHC) type II expression.
  • IL-2 production defects: These occur secondary to poorly defined defects in IL-2 production.
  • Omenn syndrome: This is associated with abnormalities in the RAG1 and RAG2 genes that are responsible for TCR and immunoglobulin rearrangement, defect in Artemis enzyme involved in VDJ rearrangement, or IL-7 receptor alpha chain gene defect.
• Usual pathogens
  • Pneumocystis jiroveci pneumonia
  • Atypical mycobacterium
  • Herpes viruses
  • Candidiasis and other systemic fungal infections
  • Cryptosporidium
  • Pneumococcus and other common bacteria

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