eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Severe Combined Immunodeficiency

Author: Smeeta Sinha, MD, Staff Physician, Department of Dermatology, UMDNJ-New Jersey Medical School
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Aug 21, 2006

Introduction

Background

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 a number of 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 with unusually severe and frequent infections by common or opportunistic pathogens. SCID is a pediatric emergency since survival depends upon expeditious stem cell reconstitution, usually by bone marrow transplantation (BMT). Alternatively, 2 forms of SCID may be successfully treated with gene therapy: X-linked SCID (XL-SCID) and adenosine deaminase (ADA)–deficient SCID.

Pathophysiology

SCID results from mutations in 1 of 10 known genes. These molecular defects block the differentiation and proliferation of T cells and, in some types, of B cells and NK cells. Antibody production is impaired severely, even when mature B cells are present. NK cells, a component of innate immunity, are affected variably. Classification of the etiologies of SCID is according to the corresponding phenotypic lymphocyte profiles: T-lymphocyte (T) negative, B-lymphocyte (B) positive, natural killer cell (NK)-negative (T^- B⁺ NK^-), T^- B^- NK^-; T^- B^- NK⁺; and T^- B⁺ NK⁺.

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 is allowed by initial failure to clear antigens appropriately.

Reticular dysgenesis is a variant of SCID characterized by bone marrow hypoplasia with resultant deficiency of both lymphocytes and hematopoietic cell lineages. Cartilage-hair hypoplasia also is classified as SCID, although a significant proportion of patients have a less severe form not requiring stem cell reconstitution.

The pathogenesis of SCID may be further delineated based on the stage or stages at which lymphopoiesis is arrested. The following 5 mechanisms reflect the known causes of SCID:

(1) Defective lymphokine signaling leading to failed cell proliferation and differentiation: An essential pathway to mature T-cell function is the g chain/janus kinase 3 (JAK3) signaling sequence. The cytokine receptors that share the common g chain include interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Cytokine binding to the g chain IL-2 and IL-7 activate the signaling pathway that includes the intracellular tyrosine kinase, JAK3.

JAK3 is up-regulated 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 common g chain or of the a chain of the IL-7 receptor, JAK3 cannot be activated; thus, cell proliferation and differentiation cannot occur. Similarly, mutations in JAK3 prevent proliferation and differentiation. Defects in the common g chain and JAK3 result in T^- B⁺ NK^- SCID, whereas IL-7 receptor a chain mutations result in T^- B^- NK⁺ SCID.

(2) Apoptosis secondary to the accumulation of toxic metabolites:Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are required for purine salvage pathways. Defects in ADA and PNP allow for the accumulation of adenosine, deoxyadenosine, and deoxyadenosine triphosphate, leading to lymphocyte toxicity and apoptosis. This results in T^- B^- NK^- SCID.

(3) Defective cell signaling at the level of the T-cell receptor (TCR) and pre-TCR: CD45, a tyrosine phosphatase found in the cell membranes of hematopoietic cells, functions in TCR and BCR signaling. Deficiency of CD45 results in T^- B⁺ NK^- SCID. CD3 is a complex of transmembrane proteins (d, g, e, and z) that forms a heterodimer with the TCR; upon ligand binding by the TCR, the immunoreceptor tyrosine-based-activation motifs (ITAMs) of CD3 become activated, which then activate the z -associated kinase (ZAP70) to propagate downstream signaling events. Deficiency of CD3 d is associated with defective pre-TCR signaling, whereas the lack of CD3 e results in the absence of mature TCRs in the periphery; both are associated with T^- B⁺ NK⁺ SCID. Defects in CD3δ result in a less severe type of immunodeficiency.

(4) Aberrant transcription or expression of cell surface molecules: The absence of cell surface major histocompatibility complex (MHC) proteins prevents normal T-cell function and communication between T cells and other effector cells. MHC class I deficiency is the result of mutations in the transporters of antigenic peptides 1 and 2 (TAP1, TAP2), and in the TAP binding protein. Defective MHC class II expression is caused by mutations in 4 regulatory genes (RFX-ANK, RFX -5, RFX-associated protein [RFXAP], CIITA) that affect transcription or inducibility of class II proteins, not by mutations in the class II genes located on chromosome 6.

(5) Deficient clonal diversity at the level of V(D)J recombination: V(D)J recombination is the process that determines the diversification of the genes encoding T-cell antigen receptors (TCRs) and B-cell antigen receptors (BCRs or immunoglobulins). The recombination activating genes RAG-1 and RAG-2 initiate V(D)J recombination, and the recombinase complex requires the product of the Artemis gene for nonhomologous end joining repair. Mutations in RAG-1, RAG-2, or Artemis cause some T^- B^- NK⁺ forms of SCID. Another gene product required for DNA cross-link repair, DCLRE1C, has been identified.

In the Omenn syndrome variant of SCID, V(D)J recombination activity is reduced. Consequently, lymphocyte counts in patients with Omenn syndrome may be normal or elevated, but many of the lymphocytes have impaired response to antigens.

In the absence of normal regulation of T-cell functions, other cell types may proliferate in an unchecked manner and become activated. Activated, anergic, oligoclonal cells that are CD4⁺ develop in some patients with common g chain or JAK3 mutations. Oligoclonal T helper 2 cells are present in Omenn syndrome, which is caused by mutations in RAG-1 and RAG-2. Autoimmunity characterizes CD3 deficiency. Hemophagocytic lymphohistiocytosis also can complicate SCID.

Murine knockout or mutated models exist for the known human mutations causing SCID and for additional components of the pathways for lymphocyte differentiation, proliferation, and cell regulation. The "SCID mouse" is very well studied for its immunologic defects and is a useful model for research in cancer and transplantation. Common g chain-/- and JAK3 -/- mice knockouts resemble human infants with SCID because abnormalities are restricted to the immune system. Murine knockouts also have been reconstituted successfully by gene transfer.

Frequency

United States

Prevalence has been estimated at 1 case per 50,000-75,000 births, but the actual incidence is not established.

International

Estimates for Europe are thought to approximate those in the United States. Cartilage-hair hypoplasia may be even more frequent in Finland.

Although SCID is notoriously underreported, several countries now maintain registries of patients with primary immunodeficiency diseases; the estimated prevalence of SCID in Australia 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.

Mortality/Morbidity

Without stem cell reconstitution, most children die in the first year of life. Allogeneic hematopoietic stem cell transplantation in patients younger than 3-4 months is associated with better outcomes.

• Early infancy is marked by recurrent failure to thrive and common infections including otitis media, diarrhea, and mucocutaneous candidiasis. If SCID is not recognized by age 6 months, opportunistic infections follow, especially Pneumocystis jiroveci pneumonia and invasive fungal infections. Common childhood viral illnesses may prove fatal, including infections with varicella, respiratory syncytial virus (RSV), rotavirus, parainfluenza virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, and adenovirus.
• In classic cases, vaccination with the attenuated oral polio strain causes 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.

Race

SCID occurs in infants throughout the world. JAK3 mutations have been reported more frequently in Italy. ZAP70 mutations are more common in Mennonite populations. MHC class II deficiency is usually reported in North African individuals. Artemis gene product deficiency is often seen in Navaho Indians of Athabascan descent. RAG-1/RAG-2 –deficient SCID occurs more commonly in Europe. Cartilage-hair hypoplasia affects a Finnish population and the old Amish order in the United States.

Sex

As noted above, 50% of SCID cases is caused by XL-SCID, mutations in the common g chain of the IL-2 receptor.

• Only about one third of males with common g chain mutations have a positive family history, indicating that patients with de novo mutations represent a significant group of people with SCID.
• The remainder of SCID cases is composed of a variety of autosomal recessive mutations; therefore, males and females are affected equally. Seek a family history of consanguinity or of an inbred population. Homologous mutations are more common in these circumstances.

Age

The great majority of SCID cases present in patients younger than 3 months.

• Patients with ADA-deficient SCID seem to have less severe mutations; some are not identified until adulthood.
• Rare patients with common g chain mutation have less severe mutations and present in the second year of life.
• Finnish patients with cartilage-hair hypoplasia may survive until later childhood or adulthood, when cancer becomes an increased risk.

Clinical

History

SCID presents during the first 3 months of life with multiple severe or recurrent illnesses such as otitis media, diarrhea, dermatitis, and before failure to thrive is present. Mucocutaneous candidiasis often is more severe than expected and resistant to treatment. Bacterial otitis media and pneumonia are common. Viral infections include varicella, herpes simplex, RSV, rotavirus, adenovirus, enterovirus, parainfluenza virus, EBV, and CMV.

• In the past, SCID was diagnosed after children developed pneumonia due to P jiroveci. Today, most infants should be recognized before appearance of failure to thrive or Pneumocystis infection.
• Diarrhea may be caused by rotavirus, adenovirus, and enterovirus. Cryptosporidiosis also is reported frequently. Diarrhea resembling Crohn disease complicates some types of SCID, such as MHC class II deficiency.
• Autoimmune phenomena, especially hemolytic anemia and neutropenia, are more common in CD3 deficiency and MHC class II mutations.
• The family history may reveal relatives who were diagnosed with SCID, multiple deaths during infancy due to infection, or unexplained deaths in male infants.
• It is important to ask the mother for risk factors for infection with human immunodeficiency virus (HIV). Infants with transplacental infection with HIV may present very similarly as those with SCID.

Physical

Examination findings are specific for the various superimposed infections and not for SCID itself. These include but are not limited to fever, tachypnea, and signs of dehydration. Patients with SCID fail to manifest palpable lymphadenopathy or tonsillar hypertrophy, findings that should raise suspicion in children with multiple aggressive infections.

• Common cutaneous findings include eczematous dermatitis that resembles severe seborrheic dermatitis, recurrent furunculosis, extensive oral thrush, and candidiasis of the diaper area. A generalized herpetic dermatitis may also be noted. Cutaneous manifestations of graft versus host disease (GVHD) may also be present from maternally derived cells that are reacting unopposed to the neonatal cells.
  • The dermatologic disorders of incontinentia pigmenti and hypohidrotic ectodermal dysplasia are associated with severe pneumococcal infections and progressive bronchiectasis, even with immunoglobulin replacement.
  • Children with Artemis-deficient SCID additionally suffer from numerous oral and genital ulcers.
  • Some patients with a mild form of JAK3-deficient SCID may note the presence of extensive cutaneous transitory warts.
• ADA deficiency is accompanied by abnormalities to ribs and vertebrae caused by defects in cartilaginous structures.
• Sparse hair, abnormal dentition, and osteopetrosis are other manifestations in these patients. Mutations in IKK-g cause these disorders, and the mouse model has both T- and B-cell dysfunction.
• Unique features of Omenn syndrome and the Omenn-like syndrome caused by GVHD include erythroderma, lymphoid hyperplasia, hypereosinophilia, and hepatosplenomegaly.

Causes

Mutational analysis pinpoints many types of SCID. Large deletions of chromosomal material are not seen, limiting 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.

SCID is most commonly due to an X-linked mutation of the gene for the IL-2 receptor g chain, which 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, and the lymphocyte profile is T^- B⁺ NK^-. Mutations in the intracellular tail of the common g chain are associated with a less severe form of XL-SCID.

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

• ADA deficiency is the second most frequent type of SCID, comprising 16% of total cases. The ADA gene is found on chromosome band 20q13.11. The lymphocyte profile is T^- B^- NK^-. ADA mutations differ among African American, Amish, and Mennonite populations.
• Mutation of the IL-7 receptor a chain causes 10% of cases, making it the third most common type of SCID. The gene for the IL-7 receptor a chain is found on chromosome band 5p13, and the lymphocyte profile is T^- B⁺ NK⁺.
• Mutation of the JAK-3 tyrosine kinase occurs in an estimated 7-14% of SCID cases. The JAK3 gene is located on chromosome band 19p13.1. The resultant lymphocyte profile is T^- B⁺ NK^-.
• Null mutations in RAG-1 and RAG-2 underlie the autosomal recessive T^- B^- NKC⁺ form of SCID. The genes map to chromosome band 11p13, and one case series estimates that RAG mutations account for 3% of SCID.
• CD45 mutations map to genes on chromosome band 1q31-1q32, resulting in the lymphocyte phenotype T^- B⁺ NK^-. This autosomal recessive etiology of SCID is very rare.
• Artemis gene mutations on chromosome band 10p13 account for approximately 1% of SCID cases. The lymphocyte phenotype is T^- B^- NK⁺.
• Mutations of ZAP-70, another tyrosine kinase, cause the CD8-deficient variant.
• CD3 g, e, and d mutations are on chromosome band 11q23. CD3 mutations collectively account for about 1% of SCID cases. The lymphocyte phenotype is T^- B⁺ NK⁺.
• MHC class II deficiency caused by CIITA is a mutation located on chromosome band 16p13; the RFX5 mutation is on chromosome band 1q21; RFXAP is on 13q.
• A paucity of CD4⁺ T cells can be caused by the absence of the MHC class II (DR, DP, DQ) proteins, or by deficiency in p56lck, a tyrosine kinase–signaling molecule in the IL-2–mediated JAK-STAT pathway important for differentiation, activation, and proliferation of T cells.
• Cartilage-hair hypoplasia is an autosomal recessive disorder localized to chromosome arm 9p.

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