Pediatric Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID) is a life-threatening syndrome of recurrent infections, diarrhea, dermatitis, and failure to thrive. It is the prototype of the primary immunodeficiency diseases and is caused by numerous molecular defects that lead to severe compromise in the number and function of T cells, B cells, and occasionally natural killer (NK) cells. Clinically, most patients present before age 3 months. Without intervention, SCID usually results in severe infection and death in children by age 2 years.

A committee of experts, initially sponsored by the World Health Organization (WHO), meets every 2 years with the goal to classify the group of primary immunodeficiency diseases according to current understanding of the pathways that become defective in the immune system. ^[1] Eight classification groups have been determined, with SCID being one of the best studied. Over the past few decades, the diverse molecular genetic causes of SCID have been identified with progress from studies of the immune system. ^[2]

SCID is considered a pediatric emergency because survival depends on expeditious stem cell reconstitution, usually by bone marrow transplantation (BMT). Appropriate diagnosis is essential because instituting proper treatment is lifesaving. Despite the heterogeneity in the pathogenesis of immune defects, common cutaneous manifestations and typical infections can provide clinical clues in diagnosing this pediatric emergency. ^[3]

Skin manifestations were prevalent in primary immunodeficiency disorders studied in 128 pediatric patients in Kuwait; skin infections were the most prevalent findings, seen in 39 patients (30%), followed by dermatitis in 24 (19%). ^[4] Skin infections were significantly more prevalent in those with congenital defects in phagocyte number, function, or both, as well as in those with well-defined immunodeficiencies.

Dermatitis was evident in all patients with hyper–immunoglobulin (Ig) E syndrome and Wiskott-Aldrich syndrome. ^[4] Erythroderma of infancy with diffuse alopecia was seen exclusively in patients with SCID disorders, and telangiectasia in patients with ataxia telangiectasia; and partial albinism with silvery gray hair was associated with Chediak-Higashi syndrome.

With the advances in BMT and gene therapy, patients now have a better likelihood of developing a functional immune system in a previously lethal genetic disease. However, once an infant develops serious infections, intervention is rarely successful.

Genetic defects

SCID results from mutations in any of more than 15 known genes. These molecular defects interfere with lymphocyte development and function, blocking the differentiation and proliferation of T cells and, in some types, of B cells and NK cells. Antibody production is severely impaired even when mature B cells are present, because of the lack of T-cell help. NK cells, a component of innate immunity, are variably affected. Sequencing and other techniques may reveal the actual genetic defects in these patients. ^[5] Ideally, SCID can be detected in a newborn before the onset of infections, with one well-documented example by screening of T-cell–receptor excision circles. ^[6]

SCID can be broadly classified into 2 groups: SCID with B cells (70% of patients with SCID) and SCID without B cells. Beyond this basic grouping, SCID may be categorized according to phenotypic lymphocyte profiles that include both B-cell status (B⁺ or B^–) and NK-cell status (NK⁺ or NK^–) in addition to T-cell status (T^–, because there is always a T-cell deficiency in SCID).

The most common genetic condition responsible for SCID is a mutation of the common γ 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^– B⁺ NK^–). ^[7] 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 [XL-SCID]). These patients account for approximately 50% of all patients with SCID. A novel pathogenic mutation on the interleukin-7 receptor has been described in a newborn. ^[8]

In X-linked SCID, loss of IL-2 receptor (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. ^{[7, 9, 10]}

Autosomal recessive SCID (formerly known as Swiss-type agammaglobulinemia) includes the following deficiencies:

• Janus-associated kinase 3 (JAK3) deficiency (T^– B⁺ NK^–) ^{[9, 10, 11, 12]}

• Adenosine deaminase (ADA) deficiency (T^– B^– NK^+/–) ^[13]

• Bare lymphocyte syndrome (a somewhat milder SCID) ^{[14, 15, 16]}

• ζ chain–associated protein (ZAP)-70 deficiency ^[17]

• Reticular dysgenesis

• IL-7R α chain deficiency

• Deficiency of the recombination-activating genes RAG1 and RAG2 (T^– B^– NK⁺) ^[18]

• Ligase 4 deficiency (T^– B^– NK⁺) ^[19]

• CD45 deficiency ^[20]

JAK3 is a protein tyrosine kinase (PTK) that associates with the common γ chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of XL-SCID. ^{[11, 12]}

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. ^[13]

Bare lymphocyte syndrome 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 entirely. The defect occurs in a gene regulating expression of MHC type II. ^{[14, 15]}

In 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 selective absence of CD8⁺ T cells and an abundance of nonfunctioning CD4⁺ T cells occur. ZAP-70 is apparently needed in the selection of CD8⁺ T cells and is necessary for T cell functioning—hence the nonfunctioning CD4⁺ cells. ^[17]

Reticular dysgenesis is a rare variant of SCID arising from the lack of appropriate stem cell development and characterized by agranulocytosis in addition to a lack of both B cells and T cells in the adaptive immune system. Mutations in mitochondrial adenylate kinase 2 have been revealed in patients with reticular dysgenesis. ^[21] Cartilage-hair hypoplasia is also classified as SCID, although a significant proportion of patients have a less severe form not requiring stem cell reconstitution.

Several deficiencies of the CD3 complex (CD3γ, ε, δ, and ζ) are associated with SCID. ^{[22, 23]} Omenn syndrome results from mutations that impair the function of Ig and TCR recombinase genes. These include the Artemis mutation ^[24] (an enzyme that opens DNA hairpin during variable diversity joining [VDJ] rearrangement) and RAG1 and RAG2 deficiencies. ^{[18, 25, 26]}

Purine nucleotide phosphorylase (PNP) deficiency and IL-2 deficiency are severe enough in nature to be classified as SCID, and other defects are identified every year. ^[27] The exact molecular defect involved in IL-2 production deficiency is unknown, but this defect is often associated with other cytokine production defects.

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 (carinii) pneumonia [PCP], systemic candidiasis, generalized herpetic infections, severe failure to thrive secondary to gut infections or diarrhea). Graft versus host disease (GVHD) from nonirradiated blood products is an important cause of morbidity.

Most patients with SCID have atrophic thymuses populated by few lymphocytes and decreased or absent Hassall corpuscles. Peripheral lymphoid tissue is usually absent or severely decreased. In some circumstances, poorly functioning activated oligoclonal lymphocytes develop, perhaps because of increased antigen stimulation that may occur due to failure of clearing antigens appropriately.

Human phosphoglucomutase 3 mutations cause a congenital severe immunodeficiency disorder associated with skeletal dysplasia. ^[28]

Pathogenetic mechanisms

The pathogenesis of SCID may be further divided into the following 5 mechanisms on the basis of the stage or stages at which lymphopoiesis is arrested.

Defective lymphokine signaling

An early block may occur within the T-cell differentiation pathway. The most common form of SCID, occurring in 40-60% of patients, is XL-SCID, which arises from defects in the common γ chain of interleukin receptors. This molecular defect results in absent T-cell and NK-cell maturation, although evidence suggests that the γ chain is also involved in B-cell development.

The cytokine receptors that share the common γ chain include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These function to increase cytokine binding affinity and signal transduction. ^{[29, 30]} Cytokine binding to the γ chain of these cytokines activate the signaling pathway that includes the intracellular tyrosine kinase JAK3. JAK3 is upregulated as the T cell is activated; downstream signaling by JAK3 triggers 3 additional signaling pathways, including the signal transducers and activators of transcription (STATs).

In the absence of the common γ chain or of the alpha chain of the IL-7 receptor, JAK3 cannot be activated in pro-T cells in the bone marrow; thus, T-cell maturation and differentiation cannot occur. Similarly, mutations in JAK3 prevent proliferation and differentiation in pro-T cells. The common γ chain is shared as a receptor of IL-15, which is a key growth factor for NK cells. Thus, defects in the common γ chain and JAK3 result in T^– B⁺ NK^– SCID, whereas IL-7 receptor alpha-chain mutations result in T^– B^– NK⁺ SCID.

In addition, defects in signaling molecules that associate with the T-cell receptor can lead to SCID; examples include mutations in the LCK and ZAP70 genes. Another cytokine receptor–associated gene is JAK1, which, when defective, can lead to SCID.

Apoptosis secondary to accumulation of toxic metabolites

Abnormal purine metabolism may be involved in the pathogenesis of SCID. ADA and PNP are required for purine salvage pathways. Defects in ADA and PNP can lead to apoptosis, resulting in T^– B^– NK^– SCID.

ADA deficiency accounts for 20% of all SCID cases. It leads to the accumulation of intermediates (eg, adenosine diphosphate, guanosine triphosphate, and dATP), which results in lymphocyte toxicity, particularly with immature thymic lymphocytes. PNP deficiency is mechanistically similar to ADA deficiency in that the accumulation of an intermediate (in this case, deoxyguanosine triphosphate [dGTP]) exerts a lymphotoxic effect. In both conditions, T-cell function is most severely affected.

Defective cell signaling at and before level of TCR

CD45, a tyrosine phosphatase found in the cell membranes of hematopoietic cells, is essential in regulating the transmission of cell surface signals in B cells and T cells. Deficiency of CD45 can lead to in T^– B⁺ NK^– SCID.

CD3 is a complex of transmembrane proteins (δ, γ, ε, and ζ) that forms a heterodimer with the TCR; upon ligand binding by the TCR, the immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 become activated, and these then activate the kinase ZAP-70 to propagate downstream signaling events.

Deficiency of CD3δ is associated with defective pre-TCR signaling, whereas the lack of CD3ε results in the absence of mature TCRs in the periphery; both are associated with T^– B⁺ NK⁺ SCID. Deficiency of ZAP-70 causes a preferential decrease of CD8 cells, causing an atypical SCID. Likewise, CD3 deficiency presents with close-to-normal absolute lymphocyte count, although these T cells are dysfunctional.

Defective expression of MHC molecules disrupts antigen (Ag) presentation at the pre-TCR level, leading to bare lymphocyte syndrome, which then results in an inability of the T cells to function. Patients with this condition can have defects in the regulatory region of the MHC class II gene or a defect in a transcription regulator, CTIIA, which is responsible for controlling the expression of MHC class II genes.

Defective TCR and Ig gene rearrangement

Abnormal TCR and Ig gene rearrangement may occur. Both B-cell maturation and T-cell maturation involve a process of recombination in which various combinations of VDJ genes are assembled to create unique and specific antigen receptors. Several recombinases play critical roles in this process.

RAG1 and RAG2, which mediate initial DNA double-strand breaking at specific sequences, enable subsequent joining of the various gene segments. Mutations in RAG1 and RAG2 result in a T^– B^– NK⁺ SCID phenotype and Omenn syndrome, in which residual VDJ recombination activity occurs. ^[26]

The ARTEMIS gene, located on chromosome 10, encodes a product that plays a role in VDJ recombination and is associated with SCID that develops from an early block in B- and T-cell development. Artemis splice defects may cause atypical relatively mild combined immunodeficiency. ^[24]

The gene DNA-PK is a DNA-dependent serine-threonine protein kinase that is required for correct recombination. Mutations in this gene are autosomal recessive and can also lead to combined deficiency. DNA from the cells of these patients is associated with an increased radiosensitivity.

Thymic dysgenesis

Severe thymic dysgenesis results in lack of T cells, causing a T^– B⁺ NK⁺ SCID. This is typically seen in severe forms of DiGeorge syndrome and CHARGE association.

Genetic mutations

Mutational analysis pinpoints many types of SCID: more than 20 genetic loci are referenced in the Online Mendelian Inheritance in Man (OMIM) database. Large deletions of chromosomal material are not seen, and this limits the techniques that can be applied for mutation detection. In general, specific mutations do not predict the degree of severity of a specific form of SCID.

Overall, SCID is characterized by profound abnormalities in T-cell, B-cell, and NK-cell functions. The genetic mutations can be X-linked, autosomal recessive, or sporadic, depending on the location of the gene affected. Although the list of gene defects is extensive, the disease can be stratified according to absence of T-cell function with or without the loss of B- and NK-cell host defenses (see Table 1 below).

Table 1. Common Causes of SCID, Cellular Defects, and Inheritance Pattern (Open Table in a new window)

SCID is most commonly due to an X-linked mutation of the gene coding for the γ chain that is common to the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XL-SCID accounts for approximately 50% of all cases of SCID. Mutations in the intracellular tail of the common γ chain are associated with a less severe form of XL-SCID. Defective expression of the common γ chain can be detected by flow cytometry. SCID has also been described due to compound heterozygous mutations in the MTHFD1 gene. ^[31] Hydroxocobalamin and folate therapy provided partial immune reconstitution.

The remainder of SCID cases result from the following autosomal recessive or, less commonly, sporadic mutations:

• ADA and PNP deficiencies

• Mutation of the IL-7R α chain

• IL-2 production defects

• Mutation of JAK3

• Null mutations in RAG1 and RAG2

• Artemis gene mutations

• CD45 mutations

• Mutations of ZAP70

• CD3γ, ε, and δ mutations

• MHC class II deficiency caused by mutations of components of the transcription factors of MHC II, including CIITA

• Bare lymphocyte syndrome

• Deficiency in p56lck (a tyrosine kinase–signaling molecule in the IL-2–mediated JAK-STAT pathway)

• Cartilage-hair hypoplasia

Opportunistic infections

Loss of immunity results in severe and opportunistic infections that instigate the rapid downhill course of SCID. Essentially, most infectious organisms can cause disease, but the following are the more common infections in SCID:

• Viral infections – Cytomegalovirus (CMV) (pneumonia, hepatitis); parainfluenza virus 3, respiratory syncytial virus (RSV), and adenovirus (pneumonia); enterovirus and rotavirus (diarrhea); varicella zoster virus (VZV), herpes simplex virus (HSV), and human herpesvirus 6 (extensive cutaneous disease, meningitis)

• Candida albicans infections – Thrush; diaper dermatitis progressing to diffuse skin involvement; renal and biliary candidiasis

• Cutaneous fungal infections

• Cryptosporidial infections

• Aspergillus infections (pneumonia)

• Bacterial infections -Staphylococcus aureus, streptococci, and enterococci (pyodermas, recurrent furunculosis, impetigo); Pseudomonas aeruginosa (ecthyma gangrenosum); Pneumocystis jiroveci (pneumonia); atypical mycobacteria; Pneumococcus and other common bacteria; Haemophilus influenzae and Listeria, Legionella, and Moraxella species

• Protozoan infections (diarrhea)

Exacerbating factors

A number of exacerbating factors may be present in patients with SCID. In most cases, the presence of maternal T cells is asymptomatic; however, approximately 30-40% of infants with SCID develop mild changes, such as erythema with skin T-cell infiltration, eosinophilia, elevated liver enzyme levels, and periportal T-cell infiltration. However, no cases of maternal graft-versus-host disease (GVHD) fatality have been reported.

GVHD can occur after engraftment of allogeneic immunocompetent lymphocytes because of incompatible bone marrow grafts or transfusion of blood products. Signs and symptoms include necrotizing erythroderma, gut mucosal abrasion, and biliary epithelium destruction.

In the past, when infants were routinely immunized with vaccinia virus, many infants with SCID died of vaccinia gangrenosa or progressive vaccinia. The bacille Calmette-Guérin (BCG) vaccine is still widely used in many countries; it can lead to a disseminated, fatal infection, revealing SCID. ^[32] Live vaccines, such as BCG and varicella vaccines, must not be administered to patients with SCID.

United States statistics

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 (closer to 1 case per 50,000-75,000 births). To the author’s knowledge, no population surveys have been performed. However, interest has been garnered in implementing screening to identify affected newborns. ^[33]

Approximately 50% of all SCID cases are X-linked (ie, mutation of the common γ 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 statistics

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

Although SCID is notoriously underreported, several countries now maintain registries of patients with primary immunodeficiency diseases. In Australia, the estimated prevalence of SCID is 0.15 case per 100,000; in Norway, 0.045 case per 100,000; and in Switzerland, 0.47 case per 100,000. In Sweden, SCID occurs in 2.43 of every 100,000 live births.

Age-related demographics

The great majority of SCID cases present in patients younger than 3 months (average age at symptom onset, 2 months; mean age at diagnosis, 6.5 months). Patients with ADA-deficient SCID seem to have less severe mutations; some are not identified until adulthood. Patients with common γ chain mutation may reveal less severe mutations and present in the second year of life but this occurs rarely. Finnish patients with cartilage-hair hypoplasia may survive until later childhood or adulthood when cancer becomes an increased risk.

Sex-related demographics

About 50% of SCID cases are X-linked (ie, occurring only in males). Only about one third of males with common γ chain mutations have a positive family history, which indicates that de novo mutations account for a significant percentage of SCID cases. The remaining SCID cases are caused by various autosomal recessive mutations that affect males and females equally. Seek a family history of consanguinity or of an inbred population. Homologous mutations are more common in these circumstances. Thus, the overall male-to-female ratio is 3:1.

Race-related demographics

No racial predisposition exists for most forms of SCID, but most patients with ZAP-70 deficiency and CD3δ are Mennonites. The Artemis gene deficiency is seen predominately in Navajo and Apache Native Americans. JAK3 mutations have been reported more frequently in Italy. MHC II deficiency is usually reported in North African individuals. RAG1/RAG2 -deficient SCID occurs more commonly in Europe. Cartilage-hair hypoplasia affects a Finnish population and the old Amish order in the United States.

Without treatment, death from infection usually occurs within the first 2 years of life. Diagnosis must be made before severe life-threatening infections occur so that the immunity can be restored with enzyme replacement or BMT; such treatment can lead to long-term survival. With bone marrow and other stem cell reconstitution techniques, many patients with SCID are fully reconstituted without complications.

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. The risk for GVHD or graft failure has declined significantly with newer techniques that include T-cell depletion using monoclonal antibodies and, possibly, the use of cord blood CD34⁺ stem cells. In selected patients with SCID, pretransplant immunosuppression is not necessary.

Patients who are well-nourished, uninfected, and younger than 6 months before transplantation have the best outcomes. Allogeneic hematopoietic stem cell transplantation (HSCT) in patients younger than 3-4 months of age is associated with better outcomes.

Patients with common γ chain (XL-SCID) or JAK3 mutations have an increased risk of hypogammaglobulinemia after transplantation because of the retention of recipient B cells that do not respond adequately to donor T-cell communication.

Although patients with SCID rarely survive without stem cell reconstitution, gene therapy may be a viable alternative for XL-SCID and ADA deficiency in patients who are unable to find donors if the complication of acute lymphoblastic leukemia is effectively prevented.

Patients with less severe ADA mutations have survived into adulthood. An optional treatment for ADA deficiency is polyethylene glycol (PEG)-treated ADA replacement, although this does not return immune function to normal.

Cartilage-hair hypoplasia, particularly in the Finnish population, may be less severe.

Early infancy is characterized by recurrent failure to thrive and a number of common infections, including otitis media, diarrhea, and opportunistic infections such as mucocutaneous candidiasis and CMV infection. If SCID is not recognized by age 6 months, opportunistic infections become more evident, especially P jiroveci pneumonia and invasive fungal infections. Common childhood viral illnesses may prove fatal in SCID. These include infections with VZV, RSV, rotavirus, parainfluenza virus, CMV, Epstein-Barr virus (EBV), enterovirus, and adenovirus.

In classic cases, vaccination with the attenuated oral polio strain causes disseminated infection and resultant death.

Some patients with cartilage-hair hypoplasia, ADA deficiency, MHC class II, or a less severe mutation in XL-SCID survive longer. The former variant is associated with a high incidence of non-Hodgkin lymphoma.

Families must be informed about the risks of infection so that appropriate steps to avoid exposure to infection are instituted. They must be cautioned not to ignore a fever, rashes, or malaise in an affected child; these may indicate a serious infection.

Parents should be instructed to ensure that the child does not receive live virus vaccines, especially polio or BCG. Vaccinating children with SCID prior to treatment is not only futile, because they cannot make antibody, but is also very dangerous. The live attenuated virus can be deadly and can lead to disease in these immunocompromised hosts.

Genetic counseling is an essential part of medical care for the family, and the opportunity for prenatal diagnosis must be discussed. Parents must be informed of the risk of SCID in subsequent children, depending on X-linked or autosomal etiology. The risk that XL-SCID will occur in another child is 50% for male infants; female infants are not affected, but they have a 50% risk of being carriers. Any autosomal recessive mutation causing SCID places siblings at a 1 in 4 risk for the disorder.

With respect to informed consent, stem cell reconstitution must be discussed carefully with the family, particularly because the donor may be a sibling who is too young to understand the risks and benefits of the procedure. Under these circumstances, a guardian outside the family may most effectively guide this decision.

Furthermore, in weighing the likelihood of death unless stem cell reconstitution is attempted, it is essential that families are made aware of the high risk of fatal infection or GVHD in the recipient after transplantation. Communicate the high risk for life-threatening infection during the preparative immunosuppressive regimen (when indicated), in addition to the risk for failure to engraft and GVHD. Adequate informed consent for stem cell reconstitution must review these points.

When patients with SCID fail to engraft or develop GVHD after transplantation, other forms of stem cell reconstitution may be considered, including cord cell transplantation. Gene therapy is an option for XL-SCID and ADA-deficient SCID.

The Immune Deficiency Foundation is an important resource for education and support for patients and families with any primary immunodeficiency disease. The current address is 25 West Chesapeake Avenue, Suite 206, Towson, MD 21204; 877-666-0866. Some US states have local chapters.

The Jeffrey Modell Foundation also provides educational support for families and patients. It is located at 747 3rd Avenue, New York, NY 10017; 800-JEFF-844 (800-533-3844).