AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Severe combined immunodeficiency (SCID) is a syndrome first coined by John Soothill, MD, in 1975 at a World Health Organization Expert Committee on primary immunodeficiency. The immunodeficiency is severe because, if unrecognized, it often proves fatal before the patient is aged 2 years, and it is combined because of a pronounced defect in both cell-mediated and humoral immunity. Therefore, patients with SCID have profound defects in the adaptive immune system, and both T-cell and B-cell functions are affected. Combined deficiencies account for approximately 20% of primary immunodeficiencies.

SCID can be classified into 2 groups: SCID with B cells (70% of patients with SCID) and SCID without B cells. T-cell function is affected in all forms of SCID. A T-cell abnormality can lead to defects in B-cell function because B cells require T-cell help for proper activation of the production of antibodies.

Over the past few decades, the diverse molecular genetic causes of SCID have been identified. Despite the heterogeneity in the pathogenesis, common cutaneous manifestations and typical infections can provide clinical clues in diagnosing this pediatric emergency. Appropriate diagnosis is essential because treatment to save the patient can be initiated. With the advances in bone marrow transplantation and gene therapy, patients now have a better likelihood of recovering normal immune function in a previously lethal genetic disease. However, once an infant develops serious infections, intervention is rarely successful.

Pathophysiology

SCID can be caused by a variety of distinct genetic defects that interfere with lymphocyte development and function. These defects lead to loss of function of both B and T cells. A defect that affects early lymphocyte development, such as progenitor cells, can lead to an inability to produce both B cells and T cells. Also, a defect of T cells alone can lead to combined immune defects because B cells are dependent on T-cell help for a response to antigen and immunoglobulin class-switching. Although novel causes of SCID continued to be revealed, the pathogenesis can be grouped into mechanisms that are related to lymphocyte development and function.

A defect in lymphoid stem cell development can lead to profound deficiency of both B cells and T cells, such as reticular dysgenesis.

An early block may occur within the T-cell differentiation pathway. The most common form, occurring in 40-60% of patients with SCID, is the X-linked form, SCID-X1, which arises from defects in the common g chain of interleukin receptors. This molecular defect results in absent T- and natural killer (NK)–cell maturation, although recent evidence suggests that the g chain is also involved in B-cell development.

The g chain is a member of the hematopoietic cytokine receptor family. Interleukin 2Ra (IL-2Ra) and interleukin 2Rb (IL-2Rb), in combination with the g chain, recruits interleukin 2 (IL-2), resulting in signal transduction by means of activation of its tyrosine kinase Janus kinase 3 (JAK3). Phosphorylation of signal transducers and activators of transcription 5 (STAT-5) proceeds, enabling its translocation to the nucleus for transcription of genes involved in cell division. Mutation of JAK3 results in the absence of T- and NK-cell function as in SCID-X1.

In addition, the g chain is a member of the interleukin 4 (IL-4), interleukin 7 (IL-7), interleukin 9 (IL-9), interleukin 15 (IL-15) and interleukin 21 (IL-21) receptors, which also function to increase cytokine binding affinity and signal transduction. 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. Other cytokine receptor–associated genes include JAK1 and JAK3, which, when defective, can lead to SCID.

Defects in the CD45 molecule, the common leukocyte antigen that functions as a protein phosphatase, can lead to SCID. CD45 is essential in regulating the transmission of cell surface signals in B cells and T cells.

Defects in the expression of the major histocompatibility complex (MHC) lead 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.

Abnormal purine metabolism may be involved. Adenosine deaminase (ADA) deficiency accounts for 20% of all SCID cases. The enzyme deficiency results in the accumulation of intermediates, such as adenosine diphosphate, guanosine triphosphate, and deoxyadenosine triphosphate (dATP), which results in lymphocyte toxicity, particularly with immature thymic lymphocytes. Purine nucleoside phosphorylase (PNP) deficiency is mechanistically similar to ADA deficiency in that the accumulation of deoxyguanosine triphosphate (dGTP) exerts a lymphotoxic effect. In both conditions, T-cell function is most severely affected.

Abnormal recombination of genes may occur. Both B-cell maturation and T-cell maturation involve a process of recombination in which various combinations of variable, diversity, and joining (VDJ) genes are assembled to create unique and specific antigen receptors. Two recombination activating genes, recombinase activating gene 1 (RAG1) and recombinase activating gene 2 (RAG2), which mediate initial DNA double-strand breaking at specific sequences, enable subsequent joining of the various gene segments. Both RAG1 and RAG2 mutations result in a T-B-NK+ SCID phenotype and Omenn syndrome, in which residual VDJ recombination activity occurs.

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.

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.

Reticular dysgenesis is a rare form of SCID that arises from the lack of appropriate stem cell development. Patients with this disease have agranulocytosis in addition to a lack of both B cells and T cells in the adaptive immune system.

Frequency

United States

To the author's knowledge, no population surveys have been performed. However, interest has been garnered in implementing screening to identify affected newborns.¹

International

The frequency is estimated to be 1 case in 50,000-500,000 births.

Mortality/Morbidity

Diagnosis must be made before severe life-threatening infections occur so that the immunity can be restored with enzyme replacement or bone marrow transplantation. Otherwise, the mortality rate is close to 100%.

Sex

Overall, the male-to-female ratio is 3:1 because some forms of SCID are X-linked, whereas other forms of SCID are autosomal recessive.

Age

The mean patient age at diagnosis is 6.5 months.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

In patients with immunodeficiency, warning signs manifest early. Within the first month of life, infants with SCID present with persistent and recurrent diarrhea, otitis, thrush, and respiratory infections. In this setting, a thorough medical and family history, with particular attention to recurrent infections, should be obtained. Inquire about a family history of primary immunodeficiency.

• Infections are more severe in children with SCID than in children with normal immunity.
• • Patients with SCID have repeated infections. The frequency may be greater than 8 per year. The patients may require antibiotics for longer than 2 months.
  • At times, patients may require intravenous antibiotics to treat an infection.
  • Patients with SCID may have recurrent deep skin or organ abscesses.
  • Defects in the cell-mediated immune system become more apparent because breastfeeding may mask the humoral immune defects during the early neonatal period.
  • T-cell defects, such as candidiasis that affects the esophagus, may occur. For example, cytomegalovirus (CMV) infection, measles, and varicella, which are usually self-limited, infect the lungs and the brain, resulting in life-threatening pneumonia, meningitis, and sepsis. Pulmonary involvement with Pneumocystis carinii pneumonia (PCP) can also be severe.
  • Persistent thrush may be present in the mouth or on the skin.
• Initially, growth appears normal, but failure to thrive with severe emaciation ensues secondary to diarrhea and chronic infections.
• The absolute lymphocyte count is less than 3000/mm³, and the proliferative response of the lymphocytes to mitogens activation is less than 10% of control values.

Physical

Physical findings are multisystemic.

• Neurologic perturbation occurs secondary to CNS infection.
• Recurrent, painful otitis media, which may be more severe than typical, is common.
• A gradually worsening bronchiolitic-type illness with a chronic cough and wheeze is present.
• Abdominal findings include tenderness secondary to gastrointestinal infections and hepatomegaly from viral hepatitis.
• Lymphadenopathy occurs with maternofetal lymphoid engraftment (MFE).
• Infants with SCID have an extensive and diverse group of cutaneous disorders. Recurrent skin abscesses are present. Candidiasis is persistent.
• Extensive candidiasis in the mouth and diaper area may persist beyond the neonatal period and may involve the rest of the skin.
• Intractable eczemalike dermatitis is noted.
• Severe seborrheic dermatitis is observed over the scalp, ears, and nasolabial folds.
• Impetigo and severe skin infections with deep ulcers in the perineum, tongue, and buccal mucosa are observed.
• Sparse hair and absence of the eyebrows and eyelashes are characteristic.
• Various cutaneous manifestations of graft versus host disease (GVHD) that ensue a few days to weeks after transfusion include the following:
• • In the acute setting, a maculopapular or morbilliform rash can occur and progress to erythroderma and exfoliative dermatitis.
  • In chronic GVHD, lichenoid or sclerodermoid lesions are described.

Causes

The syndrome is caused by more than 20 genetic loci referenced in the Online Mendelian Inheritance in Man (OMIM) database. Overall, SCID is characterized by profound abnormalities in T-, B-, 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. The Table below outlines the more common causes of SCID, the cellular defect, and the inheritance pattern.

Common Causes of SCID, Cellular Defects, and Inheritance Pattern

• 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
  • • CMV - Pneumonia, hepatitis
    • Parainfluenza virus 3, respiratory syncytial virus, adenovirus - Pneumonia
    • Enterovirus, rotavirus - Diarrhea
    • Varicella, herpes simplex, human herpesvirus 6 - Extensive cutaneous disease, meningitis
  • Candida albicans
  • • Thrush
    • Diaper dermatitis progressing to diffuse skin involvement
    • Renal and biliary candidiasis
  • Cutaneous fungal
  • Aspergillus - Pneumonia
  • Bacterial
  • • Staphylococcus aureus, streptococci, enterococci - Pyodermas, recurrent furunculosis, impetigo
    • Pseudomonas aeruginosa - Ecthyma gangrenosum
    • Pneumocystis carinii - Most common cause of SCID pneumonia
    • Haemophilus influenzae and Listeria, Legionella, and Moraxella species
  • Protozoa - Diarrhea
• Exacerbating factors include the following: 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 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. Live vaccines, such as BCG and varicella vaccines, must not be administered to patients with SCID.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

HIV and/or AIDS
Leiner disease
Letter Siwe histiocytosis
Primary immunodeficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Blood count and/or blood smear: Children with SCID have less than 3000/µL; however, a normal number of lymphocytes does not rule out SCID because the lymphocytes may be nonfunctional.
• Immunoglobulin levels, especially the M component, can be low. However, soon after birth, immunoglobulin G (IgG) levels may be falsely elevated because of maternal IgG.
• Other laboratory studies can be performed on the basis of clinical judgment, depending on the nature of the infection and the organ system involved. Specifically, assays that measure the ability of lymphocytes to respond to activating agents, such as pokeweed mitogen and phytohemagglutinin, are valuable.

Imaging Studies

• Chest radiographs usually show an absent or small thymus shadow, and they can concomitantly display lung hyperinflation with an interstitial pneumonitis or pneumonia.
• In ADA deficiency, chest radiographs show typical cupping and flaring of the costochondral junction.

Other Tests

• Amniocentesis, chorionic villous biopsy sample, or cord blood can be used for prenatal diagnosis. Recently, 2 fetuses were successfully treated with gene therapy in utero with an injection of haploidentical CD34⁺ cells for the g chain deficiency.
• Advanced assays of lymphocytes, if present, include measurements of the proliferative response of B cells and T cells to mitogens and lymphocyte subset analysis with flow cytometry. Analysis of specific genes associated with immunodeficiency may be helpful.
• Test results may confirm the lack of a delay-type hypersensitivity cellular response to mumps, purified protein derivative (PPD), Candida species, and/or Trichophyton species.
• The lack of an antibody response to tetanus toxoid may be observed.

Histologic Findings

• The thymus is small with few thymocytes, and it lacks corticomedullary distinction and Hassall corpuscles. The epithelium is normal.
• The spleen is depleted of lymphocytes.
• The lymph nodes, tonsils, adenoids, and Peyer patches are underdeveloped or absent.
• The epidermis can have foci of hyperkeratosis, with parakeratosis, or irregular acanthosis, with spongiosis and exocytosis. The papular dermis has edema and a diffuse perivascular infiltrate with some eosinophils.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The only cure is bone marrow transplantation. HLA-identical donor bone marrow transplantation is optimal, followed by HLA-matched unrelated donor transplantation. HLA-mismatched related donor transplantation is an alternative and can often be successful if an HLA-matched donor cannot be identified.

• This approach is successful if the disease is diagnosed within their first 3 months of life.
• Neither pretransplantation chemoablation nor GVHD prophylaxis is required for successful engraftment with an identical donor; however, pretransplantation myeloablation is necessary in nonidentical HLA-matched donors.
• All blood products must receive 25-Gy irradiation to prevent fatal GVHD. Advances in gene therapy should lead to the correction of single genetic defects in lymphocytes.
• No live vaccines, such as the BCG vaccine, should be administered to patients with SCID prior to bone marrow transplantation.
• Several gene therapy clinical trials based on gene transfer to hematopoietic cells have been performed, but these approaches still require further development before becoming routine protocols.^{2, 3}

Consultations

• Consultation with an internal medicine specialist and an infectious disease specialist is important in the management and prevention of infection.
• A hematologist and/or an oncologist should be consulted for bone marrow transplantation.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

SCID is best managed with stem cell replacement to reconstitute a functional immune system. For disorders caused by a single-gene defect, gene replacement in stem cells may offer a better prognosis. Without an effective immune system, patients with SCID have a poor prognosis, and management requires preventive prophylaxis of infections due to common pathogens and vigilant monitoring of potential infections. Immediate treatment upon the diagnosis of new infections is critical. Patients with known enzyme deficiency, such as ADA deficiency, may receive enzyme replacement. Also, intravenous immunoglobulin (IVIG) may help prevent symptoms of common infectious disorders.

Drug Category: Intravenous immunoglobulin

IVIG can be used to restore antibody levels until the B-cell system is restored with transplantation. However, long-term use fails to change the terminal course of SCID.

Drug Category: Antibiotics

Antibiotics are used in the primary treatment and prophylaxis of PCP pneumonia.

Drug Category: Enzyme replacement

These agents are used in patients with ADA deficiency and SCID who benefit from bone marrow transplantation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Ensure regular follow-up visits to monitor the immune system, with specialist physicians monitoring the patient.

In/Out Patient Meds

• Patients require prophylactic antibiotics and IVIG prior to bone marrow replacement.
• Patients who have ADA deficiency need enzyme replacement therapy. Patients need to have their immune function monitored and prophylaxis provided depending on their immune status.
• For those patients who underwent bone marrow transplantation, medication therapy to prevent GVHD must be maintained.⁴

Complications

• Patients who receive bone marrow transplants develop GVHD and the adverse effects of the medications necessary to control GVHD.
• Patients are at risk for infections from inadequate immune reconstitution from bone marrow transplantation or enzyme replacement. Gene therapy has been associated with virus-induced malignancies.

Prognosis

• Untreated SCID is fatal.
• Treatment with bone marrow transplantation or enzyme replacement to reconstitute the immune system can lead to long-term survival.

Patient Education

• For information and links to other useful sites and for information regarding a support group, see the Severe Combined Immunodeficiency Web site.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose the condition

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Puck JM,. Population-based newborn screening for severe combined immunodeficiency: steps toward implementation. J Allergy Clin Immunol. Oct 2007;120(4):760-8. [Medline].
2. Ariga T. Gene therapy for primary immunodeficiency diseases: recent progress and misgivings. Curr Pharm Des. 2006;12(5):549-56. [Medline].
3. Fischer A, Hacein-Bey S, Le Deist F, de Saint Basile G, Cavazzana-Calvo M. Gene therapy for human severe combined immunodeficiencies. Immunity. Jul 2001;15(1):1-4. [Medline].
4. Friedrich W, Hönig M, Müller SM. Long-term follow-up in patients with severe combined immunodeficiency treated by bone marrow transplantation. Immunol Res. 2007;38(1-3):165-73. [Medline].
5. Bonilla FA, Geha RS. 2. Update on primary immunodeficiency diseases. J Allergy Clin Immunol. Feb 2006;117(2 Suppl Mini-Primer):S435-41. [Medline].
6. Buckley RH, Schiff RI, Schiff SE, Markert ML, Williams LW, Harville TO, et al. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. Mar 1997;130(3):378-87. [Medline].
7. Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. Feb 18 1999;340(7):508-16. [Medline].
8. De Raeve L, Song M, Levy J, Mascart-Lemone F. Cutaneous lesions as a clue to severe combined immunodeficiency. Pediatr Dermatol. Mar 1992;9(1):49-51. [Medline].
9. Fischer A. Primary immunodeficiency diseases: an experimental model for molecular medicine. Lancet. Jun 9 2001;357(9271):1863-9. [Medline].
10. Gaspar HB, Gilmour KC, Jones AM. Severe combined immunodeficiency--molecular pathogenesis and diagnosis. Arch Dis Child. Feb 2001;84(2):169-73. [Medline].
11. Gennery AR, Cant AJ. Diagnosis of severe combined immunodeficiency. J Clin Pathol. Mar 2001;54(3):191-5. [Medline].
12. Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, et al. Bone marrow transplantation for severe combined immune deficiency. JAMA. Feb 1 2006;295(5):508-18. [Medline].
13. Kovanen PE, Leonard WJ. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. Immunol Rev. Dec 2004;202:67-83. [Medline].
14. Postigo Llorente C, Ivars Amorós J, Ortiz de Frutos FJ, Regueiro JR, Llamas Martín R, Guerra Tapia A, et al. Cutaneous lesions in severe combined immunodeficiency: two case reports and a review of the literature. Pediatr Dermatol. Dec 1991;8(4):314-21. [Medline].
15. Roifman CM, Zhang J, Chitayat D, Sharfe N. A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency. Blood. Oct 15 2000;96(8):2803-7. [Medline].
16. Rosen FS. Severe combined immunodeficiency: a pediatric emergency. J Pediatr. Mar 1997;130(3):345-6. [Medline].
17. Tsuji Y, Imai K, Kajiwara M, Aoki Y, Isoda T, Tomizawa D, et al. Hematopoietic stem cell transplantation for 30 patients with primary immunodeficiency diseases: 20 years experience of a single team. Bone Marrow Transplant. Mar 2006;37(5):469-77. [Medline].

Article Last Updated: Nov 8, 2007