eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Severe Combined Immunodeficiency

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

Updated: Aug 18, 2009

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 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 with unusually severe and frequent infections by common or opportunistic pathogens.

Severe combined immunodeficiency is a pediatric emergency because survival depends on expeditious stem cell reconstitution, usually by bone marrow transplantation (BMT). Alternatively, 2 forms of severe combined immunodeficiency may be successfully treated with gene therapy: X-linked severe combined immunodeficiency (XL-SCID) and adenosine deaminase (ADA)–deficient severe combined immunodeficiency.

Pathophysiology

Severe combined immunodeficiency results from mutations in one of more than 15 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 severely impaired, even when mature B cells are present due to lack of T-cell help. NK cells, a component of innate immunity, are variably affected. Classification of the etiologies of severe combined immunodeficiency is according to the corresponding phenotypic lymphocyte profiles: T-lymphocyte negative (T^-), B-lymphocyte positive (B⁺), and NK-negative (T^- B⁺ NK^-); T^- B^- NK^-; T^- B^- NK⁺; and T^- B⁺ NK⁺.

Most patients with severe combined immunodeficiency 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.

Reticular dysgenesis is a variant of severe combined immunodeficiency characterized by bone marrow hypoplasia with resultant deficiency of both lymphocytes and hematopoietic cell lineages. Recently mutations in mitochondrial adenylate kinase 2 was revealed in patients with reticular dysgenesis.¹ Cartilage-hair hypoplasia is also classified as severe combined immunodeficiency, although a significant proportion of patients have a less severe form not requiring stem cell reconstitution.

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

• Defective lymphokine signaling leading to failed cell proliferation and differentiation
  • An essential pathway to mature T-cell function is the γ chain/janus kinase 3 (JAK3) signaling sequence.
  • The cytokine receptors that share the common γ chain include interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Cytokine binding to the γ chain of these cytokines 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 γ chain or of the α chain of the IL-7 receptor, JAK3 cannot be activated in pro T cells in the bone marrow; thus, T-cell maturation/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^- severe combined immunodeficiency, whereas IL-7 receptor a chain mutations result in T^- B^- NK⁺ severe combined immunodeficiency. 
• 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^- severe combined immunodeficiency.
• 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⁺ severe combined immunodeficiency. Deficiency of ZAP70 causes a preferential decrease of CD8 cells, causing an atypical severe combined immunodeficiency.
  • Likewise, CD3 deficiency presents with close-to-normal absolute lymphocyte count, albeit these T cells are dysfunctional. 
  • Defective expression of major histocompatibility complex (MHC) molecules disrupts antigen (Ag) presentation at pre-TCR level; these involve bare lymphocyte syndrome and mutations that cause defects in expression of MHCI or MHCII molecules, causing decreased CD8 and CD4 T cells, respectively.
• Defect in TCR and Ig gene rearrangement: Both T cell and B cell requires TCR and Ig gene rearrangement in early stage of their differentiation. Several recombinases play critical roles in TCR and Ig gene rearrangement; thus, deficiency of recombinases result in T^- B^- NK⁺ severe combined immunodeficiency. Mutations in RAG1, RAG2, and Artemis genes are now shown to cause this type of severe combined immunodeficiency.
• Thymic dysgenesis: Severe thymic dysgenesis results in lack of T cells, causing a T^- B⁺ NK⁺ severe combined immunodeficiency. This is typically seen in severe forms of DiGeorge syndrome and CHARGE association. 

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 severe combined immunodeficiency is notoriously underreported, several countries now maintain registries of patients with primary immunodeficiency diseases; the estimated prevalence of severe combined immunodeficiency 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, severe combined immunodeficiency occurs in 2.43 of every 100,000 live births.

Mortality/Morbidity

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

Early infancy is characterized by recurrent failure to thrive and common infections including otitis media, diarrhea, and opportunistic infections such as mucocutaneous candidiasis and cytomegalovirus (CMV) infection. If severe combined immunodeficiency is not recognized by age 6 months, opportunistic infections become more evident, especially Pneumocystis jiroveci pneumonia and invasive fungal infections. Common childhood viral illnesses may prove fatal in severe combined immunodeficiency patients. These include infections with varicella, respiratory syncytial virus (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-severe combined immunodeficiency survive longer. The former variant is associated with a high incidence of non-Hodgkin lymphoma.

Race

Severe combined immunodeficiency 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 Athabaskan descent. RAG-1/RAG-2 –deficient severe combined immunodeficiency 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 severe combined immunodeficiency cases is caused by XL-severe combined immunodeficiency, mutations in the common γ chain shared by several cytokine receptors. Only about one third of males with common γ chain mutations have a positive family history, indicating that patients with de novo mutations represent a significant group of people with severe combined immunodeficiency. The remainder of severe combined immunodeficiency cases are composed of various 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 severe combined immunodeficiency cases present in patients younger than 3 months. Patients with ADA-deficient severe combined immunodeficiency 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.

Clinical

History

Patients with severe combined immunodeficiency (SCID) may present with multiple severe or recurrent illnesses such as otitis media, diarrhea, and dermatitis during the first 3 months of life before failure to thrive develops. Mucocutaneous candidiasis is often more severe than expected and is resistant to treatment. Bacterial otitis media and pneumonia are common. Viral infections include varicella, herpes simplex, respiratory syncytial virus (RSV), rotavirus, adenovirus, enterovirus, parainfluenza virus, Epstein-Barr virus (EBV), and cytomegalovirus (CMV).

• In the past, severe combined immunodeficiency was often diagnosed after children developed serious infections such as 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 is also reported frequently. Diarrhea resembling Crohn Disease complicates some types of SCID, such as major histocompatibility complex (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 severe combined immunodeficiency, multiple deaths during infancy due to infection, or unexplained deaths in male infants.
• Asking the mother for risk factors for infection with human immunodeficiency virus (HIV) is important. Infants with transplacental infection with HIV may present very similar to those with severe combined immunodeficiency.

Physical

Examination findings are specific for the various superimposed infections and not for severe combined immunodeficiency itself. These include but are not limited to fever, tachypnea, failure to thrive, and signs of dehydration. Patients with severe combined immunodeficiency fail to manifest palpable lymphadenopathy or tonsillar hypertrophy. Lack of recognizable peripheral lymphoid organs should raise suspicion of severe combined immunodeficiency 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 T cells that are reacting host cells in the absence of opposing host T cells.
  • The dermatologic disorders of incontinentia pigmenti and hypohidrotic ectodermal dysplasia are associated with severe pneumococcal infections and progressive bronchiectasis, even with immunoglobulin replacement.
  • Dermatophytosis is uncommon in these patients, although one was recently described with widespread tinea corporis due to Trichophyton mentagrophytes.²
  • Children with Artemis-deficient severe combined immunodeficiency additionally suffer from numerous oral and genital ulcers.
  • Some patients with a mild form of JAK3-deficient severe combined immunodeficiency may present with extensive cutaneous transitory warts.
• Adenosine deaminase (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. Hypomorphic heterozygous mutations in IKBA causes autosomal recessive ectodermal dysplasia with immunodeficiency (AD-EDA-ID) with impaired NFkB signaling pathways; however, this defect also causes severely impaired T-cell receptor (TCR) signaling with resultant clinical phenotype of severe combined immunodeficiency.
• Unique features of Omenn syndrome (OS) and the Omennlike syndrome caused by GVHD include erythroderma, lymphoid hyperplasia, hypereosinophilia, and hepatosplenomegaly. Growing numbers of leaky severe combined immunodeficiency mutations are now shown to manifest OS; thus, OS is now considered to be dysregulated inflammatory processes revealed in leaky severe combined immunodeficiency.

Causes

Mutational analysis pinpoints many types of severe combined immunodeficiency. 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 severe combined immunodeficiency.

Severe combined immunodeficiency is most commonly due to an X-linked mutation of the gene coding for common γ chain, which is common to the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. X-linked (XL) severe combined immunodeficiency accounts for approximately 50% of all cases of severe combined immunodeficiency, and the lymphocyte profile is T^- B⁺ NK^-. Mutations in the intracellular tail of the common γ chain are associated with a less severe form of XL severe combined immunodeficiency. Defective expression of common γ chain can be detected by flow cytometry

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

• ADA deficiency is the second most frequent type of severe combined immunodeficiency, 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 black, Amish, and Mennonite populations.
• Mutation of the IL-7 receptor a chain causes 10% of cases, making it the third most common type of severe combined immunodeficiency. The gene for the IL-7 receptor α 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 severe combined immunodeficiency 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 severe combined immunodeficiency. The genes map to chromosome band 11p13, and one case series estimates that RAG mutations account for 3% of severe combined immunodeficiency cases.
• CD45 mutations map to genes on chromosome band 1q31-1q32, resulting in the lymphocyte phenotype T^- B⁺ NK^-. This autosomal recessive etiology of severe combined immunodeficiency is very rare.
• Artemis gene mutations on chromosome band 10p13 account for approximately 1% of severe combined immunodeficiency cases. The lymphocyte phenotype is T^- B^- NK⁺.
• Mutations of ZAP-70, another tyrosine kinase, cause the CD8-deficient severe combined immunodeficiency variant.
• CD3 g, e, and d mutations are on chromosome band 11q23. CD3 mutations collectively account for about 1% of severe combined immunodeficiency cases. The lymphocyte phenotype is T^- B⁺ NK⁺.
• MHC class II deficiency caused by mutations of components of the transcription factors of MHCII including CIITA. CIITA is located on chromosome band 16p13; the RFX5 (another component of MHCII transcription factor) 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 and genes associated with this severe combined immunodeficiency localized to chromosome 9p.

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