eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

Severe Combined Immunodeficiency

Elizabeth A Secord, MD, Clinical Associate Professor, Department of Pediatrics, Division of Pediatric Immunology, Wayne State University
Eyal Oren, MD, Consulting Staff, Institute for Asthma and Allergy

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

Differential Diagnoses

Combined B-Cell and T-Cell Disorders
DiGeorge Syndrome

Other Problems to Be Considered

Perinatally transmitted HIV disease
Congenital TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex, or other infections) infection

Although B-cell defects usually manifest later than T-cell defects (ie, after maternal antibody wanes), also consider Bruton or X-linked agammaglobulinemia, autosomal recessive forms of agammaglobulinemia, Wiskott-Aldrich syndrome, and other forms of hypogammaglobulinemia.

Workup

Laboratory Studies

• Screening tests
  • Some states now screen all neonates for the most common forms of severe combined immunodeficiency (SCID) by identifying T-cell receptor excision circles (TRECs). TRECs are a normal byproduct of T-cell receptor rearrangement. 
  • In healthy neonates, TRECs are made in large numbers, while in infants with SCID they are barely detectable, making this a reasonable screening test for SCID. This allows identification and bone marrow transplant (BMT) before the infants become ill and greatly increases their chance of survival.¹⁸
  • A more recent study explores the use of microarray technology to identify the more common forms of SCID.¹⁹ A combination of these therapies may be the eventual solution to the dilemma of screening for SCID.
• Initial workup
  • Conduct a complete blood cell (CBC) count with differential to help detect lymphopenia. An absolute lymphocyte count of less than 2500 cells/mL in an infant definitely warrants further workup, but any infant with severe infection or opportunistic infection should have the full initial workup.
  • Draw lymphocyte markers at the same time as the CBC count to obtain percentages and absolute counts of CD3⁺ T cells, CD4⁺ T cells, CD8⁺ T cells, CD19⁺ B cells, and natural killer (NK) cell markers (CD16 and CD56).
  • Obtain total serum immunoglobulin (Ig) levels of IgG, IgA, IgM, and IgE.
  • To test lymphocyte function, assess for antibodies to standard protein vaccines (eg, diphtheria and tetanus; children <2 y cannot adequately make antibody to polysaccharide so only antibody against protein is relevant) with preimmunization and postimmunization titers. If maternal antibody is still present, which is likely, remember that this confounds the results. Check isohemagglutinins (IgM against blood group antigens), and check mitogen stimulation of lymphocytes. Patients with SCID essentially have no antibody formation and have very poor proliferation of lymphocytes. Children with IL-2 deficiency have proliferation of lymphocytes if IL-2 is added to their lymphocytes. Children with combined immune deficiency that is not severe may be difficult to differentiate from children with SCID in these initial evaluations.
  • To exclude HIV infection, perform HIV-DNA testing using polymerase chain reaction because antibody tests for HIV are of no value in this setting due to maternal antibody. To help exclude congenital infection, perform serum testing of IgM against any suspected infection. Children with complete DiGeorge syndrome have normal B-cell function, but T cells are absent or nearly absent and, if present, function poorly.
• Confirmatory tests
  • After finding abnormalities consistent with SCID, perform confirmatory tests to determine the type of SCID that is responsible.
  • Determine the adenosine deaminase (ADA) and purinenucleotide (PNP) levels in lymphocytes, erythrocytes, or fibroblasts.
  • Consider X-inactivation studies to determine whether the SCID is X-linked. Approximately 50% of patients have sporadic mutations with no history of affected family members.
  • Perform molecular studies to identify any specific known genetic defects or to identify new defects. These tests are now commercially available. If identifying a laboratory to perform these tests is difficult, consult a referral center for primary immune deficiency to assist in this matter.

Imaging Studies

• Imaging studies are not useful for diagnosis of the primary condition; however, obtaining a chest radiograph may be necessary to evaluate pneumonia secondary to SCID.

Procedures

• Only blood studies are necessary to make the initial diagnosis.

Histologic Findings

• Although a lymph node biopsy is not necessary for diagnosis, findings may indicate a paucity of T and B cells and a lack of germinal centers.

Treatment

Medical Care

• Severe combined immunodeficiency (SCID) is a pediatric emergency and must be worked up and treated promptly. Intravenous immunoglobulin (IVIG) should be administered promptly, and evaluation for bone marrow transplantation (BMT) should be started. Patients with SCID who are treated with BMT before the age of 3.5 months have markedly improved survival rates.
• Prophylaxis
  • Because T cells are absent and/or dysfunctional, administer Pneumocystis jiroveci pneumonia prophylaxis to all patients until T-cell function is restored by a BMT or other therapy.
  • Trimethoprim-sulfamethoxazole is the drug of choice and can be administered in a patient who is older than 2 months or in whom neonatal jaundice is no longer a concern.
• X-linked SCID and Janus-associated kinase 3 (JAK3) protein tyrosine kinase (PTK) deficiency
  • A BMT is the primary treatment of choice for most types of SCID when an appropriate donor is found. Pretreatment with ablative chemotherapy is controversial.
  • If B cells do not engraft, the patient may require monthly IVIG replacement therapy.
• Adenosine deaminase (ADA) deficiency
  • The primary treatment is ongoing polyethylene glycol–conjugated ADA replacement (PEG-ADA) therapy.
  • Gene therapy is in the experimental phase. Although some long-term benefits of gene therapy have been reported for ADA-deficient patients with SCID, serious complications have arisen in some cases of gene therapy in patients with common gamma chain deficiency.
  • The development of leukemia is a complication of gene therapy and appears to be related to the site of insertion of the transgene. Some suggest that better outcomes may occur with different vectors or more specific insertion sites.²⁰ Greater risk for cognitive abnormalities and emotional and behavioral problems has also been reported in ADA-deficient patients with SCID who received long-term enzyme replacement therapy.²¹
• Purinenucleotide phosphorylase (PNP) deficiency and bare lymphocyte syndrome: A BMT is the primary therapy when an appropriate donor is available.
• IL-2 production defects: Intravenous IL-2 replacement is the primary therapy, and a BMT is an alternative if an appropriate donor is available.
• Omenn syndrome: A BMT is the primary treatment; however, pretreatment ablative chemotherapy is necessary because of maternal cell engraftment.

Surgical Care

Surgical care is not part of the primary treatment.

Consultations

• Immunologist for diagnosis and treatment
• Hematology/immunology transplant team for an anticipated BMT

Diet

No diet limitations are necessary.

Activity

Only infections secondary to the immune deficiency limit activity. The disease itself does not require limitation of physical activity. Keep children with SCID in reverse isolation until BMT or other therapy is initiated.

Medication

Drug therapy is not a major part of therapy for the primary disease. Trimethoprim-sulfamethoxazole is prescribed routinely after the second month of life in children with severe combined immunodeficiency (SCID) until after bone marrow transplant (BMT) engraftment. This is Pneumocystis jiroveci prophylaxis. Intravenous immunoglobulin (IVIG) is used to prevent infection prior to BMT and, in selected patients, after BMT, if B-cell function remains poor.

Antibiotics

These agents are used as prophylaxis against Pneumocystis jiroveci pneumonia.

Trimethoprim-Sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)

Used because of low levels of T cells or poor T-cell function in children with SCID.

Dosing

Adult

1 DS tab PO bid

Pediatric

5-10 mg/kg PO divided bid 3 times per wk (Mon, Wed, Fri or Mon, Tue, Wed)

Interactions

May increase PT when used with warfarin (perform coagulation tests and adjust dose accordingly); coadministration with dapsone may increase blood levels of both drugs; coadministration of diuretics increases incidence of thrombocytopenia purpura in elderly; phenytoin levels may increase with coadministration; may potentiate effects of methotrexate in bone marrow depression; hypoglycemic response to sulfonylureas may increase with coadministration; may increase levels of zidovudine

Contraindications

Documented hypersensitivity; G-6-PD deficiency, children <2 mo, porphyria

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Can cause bone marrow suppression; hypersensitivity; hemolysis in patients with G-6-PD deficiency; use with caution in renal or hepatic failure

Immune globulins

IVIG is the usual choice. It is derived from human plasma and is composed of all 4 IgG subclasses. The antibody distribution of IVIG is approximately the same as human serum.

Intravenous immunoglobulins (Gammaimmune, Gammagard, Sandoglobulin)

Pooled human immunoglobulin provides IgG antibodies the patient cannot make.

Dosing

Adult

400-500 mg/kg IV titrating trough IgG level to 900-1000 mg/dL. This is usually administered every 3-4 wk, but frequency of administration should also be titrated to keep desired level.

Pediatric

Not established; administer as in adults

Interactions

Interferes with efficacy of MMR vaccine, but this should not be an issue in a child who does not make antibody since no vaccines are administered to these children; the IVIG replaces antibodies that vaccines would stimulate the production of in a healthy child; furthermore, live viral vaccines are contraindicated in these patients

Contraindications

Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d)
Increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Follow-up

Further Outpatient Care

• Admit the patient to an immunology/hematology clinic for intravenous immunoglobulin (IVIG) therapy, IL-2 infusion, or polyethylene glycol–conjugated adenosine deaminase replacement (PEG-ADA) therapy, as necessary.
• Frequently monitor the patient for acquired infections.

Deterrence/Prevention

• Genetic counseling is necessary. If the family wishes to have other children, suggest that they obtain prenatal testing (eg, chorionic villus sampling) if the genetic defect is known.
• Screening tests do not prevent severe combined immunodeficiency (SCID) but can identify infants early prior to complications and can allow early treatment.
• Some states now screen all neonates for the most common forms of SCID by identifying T-cell receptor excision circles (TRECs).
  • TRECs are a normal byproduct of T-cell receptor rearrangement.
  • In healthy neonates, TRECs are made in large numbers. In infants with SCID, they are barely detectable, making this a reasonable screening test for SCID.
  • This allows identification and bone marrow transplant (BMT) before the infants become ill and greatly increases their chance of survival.¹⁹
• Microarray technology has also been proposed as a screening tool to detect the most common genetic defects leading to SCID.²⁰

Complications

• Graft versus host disease (GVHD) may ensue if the blood products given prior to a bone marrow transplant (BMT) are not depleted of white blood cells by filtration or irradiation. Ensure that all blood products are also negative for cytomegalovirus to avoid systemic cytomegalovirus disease.
• Ensure that the child does not receive any live virus vaccines until after BMT engraftment, especially polio or bacille Calmette-Guérin (BCG). Vaccinating children with SCID is not only futile, because they cannot make antibody, but is also dangerous, because they can develop disease from attenuated viruses and may even die after exposure to these vaccines.

Prognosis

• Without treatment, death is expected to occur within 2 years. Following a successful bone marrow or other transplant, the patient may survive to adulthood.

Patient Education

• Parents of children with any immune deficiency can obtain information from the Immune Deficiency Foundation.
• Parents must not ignore a fever, rashes, or malaise in an affected child. These may indicate a serious infection.
• Instruct parents 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.
• For excellent patient education resources, visit eMedicine's Yeast and Fungal Infections Center. Also, see eMedicine's patient education article Candidiasis (Yeast Infection).

Miscellaneous

Medicolegal Pitfalls

• Failure to make the diagnosis because the child is not frankly lymphopenic may present a problem, particularly in patients with Omenn syndrome, bare lymphocyte syndrome, and interleukin (IL)-2 deficiency. Obtaining lymphocyte markers and test results of antibody and lymphocyte proliferation can help physicians to avoid this pitfall.
• Ensure that the child does not receive any live virus vaccines, especially polio or bacille Calmette-Gu é rin (BCG). Vaccinating children with severe combined immunodeficiency (SCID) is futile and may be very dangerous because these children can develop disease from attenuated viruses, and they may even die after exposure to these vaccines.

References

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9. Mach B, Steimle V, Reith W. MHC class II-deficient combined immunodeficiency: a disease of gene regulation. Immunol Rev. Apr 1994;138:207-21. [Medline].

10. Elder ME, Lin D, Clever J, et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science. Jun 10 1994;264(5165):1596-9. [Medline].

11. Villa A, Santagata S, Bozzi F, Imberti L, Notarangelo LD. Omenn syndrome: a disorder of Rag1 and Rag2 genes. J Clin Immunol. Mar 1999;19(2):87-97. [Medline].

12. O'Driscoll M, Cerosaletti KM, Girard PM, et al. DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell. Dec 2001;8(6):1175-85. [Medline].

13. Kung C, Pingel JT, Heikinheimo M, et al. Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med. Mar 2000;6(3):343-5. [Medline].

14. Rieux-Laucat F, Hivroz C, Lim A, et al. Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency. N Engl J Med. May 4 2006;354(18):1913-21. [Medline].

15. Dadi HK, Simon AJ, Roifman CM. Effect of CD3delta deficiency on maturation of alpha/beta and gamma/delta T-cell lineages in severe combined immunodeficiency. N Engl J Med. Nov 6 2003;349(19):1821-8. [Medline].

16. Ege M, Ma Y, Manfras B, Kalwak K, Lu H, Lieber MR. Omenn syndrome due to ARTEMIS mutations. Blood. Jun 1 2005;105(11):4179-86. [Medline].

17. Hitzig WH, Landolt R, Müller G, Bodmer P. Heterogeneity of phenotypic expression in a family with Swiss-type agammaglobulinemia: observations on the acquisition of agammaglobulinemia. J Pediatr. Jun 1971;78(6):968-80. [Medline].

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Keywords

SCID, severe combined immunodeficiency, T-cell dysfunction, T cell dysfunction, B-cell dysfunction, B cell dysfunction, graft versus host disease, GVHD, graft-versus-host disease, graft-vs-host disease, severe infection, Swiss-type agammaglobulinemia, Janus-associated kinase 3 deficiency, JAK3 deficiency, adenosine deaminase deficiency, ADA deficiency, purine nucleoside phosphorylase deficiency, PNP deficiency, bare lymphocyte syndrome, interleukin-2 deficiency, IL-2 deficiency, ZAP-70 protein tyrosine kinase deficiency, PTK deficiency, reticular dysgenesis, Omenn syndrome, Pneumocystis carinii/jiroveci pneumonia, PCP, systemic candidiasis, generalized herpetic infections, ARTEMIS, Artemis, RAG1 deficiency, RAG2 deficiency

Contributor Information and Disclosures

Author

Elizabeth A Secord, MD, Clinical Associate Professor, Department of Pediatrics, Division of Pediatric Immunology, Wayne State University
Elizabeth A Secord, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and American Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Eyal Oren, MD, Consulting Staff, Institute for Asthma and Allergy
Eyal Oren, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology and American College of Allergy, Asthma and Immunology
Disclosure: Nothing to disclose.

Medical Editor

Charles H Kirkpatrick, MD, Professor of Medicine and Immunology, University of Colorado School of Medicine; Director of Adult Immune Deficiency Program, Department of Medicine, University of Colorado Health Sciences Center; Consulting Staff, Department of Medicine, National Jewish Medical and Research Center
Charles H Kirkpatrick, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Physicians, American Federation for Clinical Research, American Society for Clinical Investigation, and Clinical Immunology Society
Disclosure: Lev Pharmaceuticals Consulting fee Consulting

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Stephen C Dreskin, MD, PhD, Director of Allergy, Asthma, and Immunology Practice, Professor of Medicine, Departments of Internal Medicine and Immunology, University of Colorado Health Sciences Center
Stephen C Dreskin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American Association of Immunologists, American Association of Neuropathologists, American Association of Ophthalmic Pathologists, American Association of Oral and Maxillofacial Surgeons, American College of Allergy, Asthma and Immunology, Clinical Immunology Society, and Joint Council of Allergy, Asthma and Immunology
Disclosure: Genentech Consulting fee Consulting

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva  Consulting; Meda Honoraria Speaking and teaching

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