eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

Severe Combined Immunodeficiency: Differential Diagnoses & Workup

Author: Elizabeth A Secord, MD, Clinical Associate Professor, Department of Pediatrics, Division of Pediatric Immunology, Wayne State University
Coauthor(s): Eyal Oren, MD, Consulting Staff, Institute for Asthma and Allergy
Contributor Information and Disclosures

Updated: May 5, 2009

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.

More on Severe Combined Immunodeficiency

Overview: Severe Combined Immunodeficiency
Differential Diagnoses & Workup: Severe Combined Immunodeficiency
Treatment & Medication: Severe Combined Immunodeficiency
Follow-up: Severe Combined Immunodeficiency
References
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References

  1. Fischer A. Severe combined immunodeficiencies. Immunodefic Rev. 1992;3(2):83-100. [Medline].

  2. Uribe L, Weinberg KI. X-linked SCID and other defects of cytokine pathways. Semin Hematol. Oct 1998;35(4):299-309. [Medline].

  3. Hong R. Disorders of the T cell system. In: Stiehm ER, ed. Immunologic Disorders in Infants and Children. 4th ed. Philadelphia, Pa: WB Saunders; 1996:339-408.

  4. Macchi P, Villa A, Giliani S, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. Sep 7 1995;377(6544):65-8. [Medline].

  5. Candotti F, O'Shea JJ, Villa A. Severe combined immune deficiencies due to defects of the common gamma chain-JAK3 signaling pathway. Springer Semin Immunopathol. 1998;19(4):401-15. [Medline].

  6. Hirschhorn R, Vawter GF, Kirkpatrick JA Jr, Rosen FS. Adenosine deaminase deficiency: frequency and comparative pathology in autosomally recessive severe combined immunodeficiency. Clin Immunol Immunopathol. Sep 1979;14(1):107-20. [Medline].

  7. Reith W, Mach B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu Rev Immunol. 2001;19:331-73. [Medline].

  8. DeSandro A, Nagarajan UM, Boss JM. The bare lymphocyte syndrome: molecular clues to the transcriptional regulation of major histocompatibility complex class II genes. Am J Hum Genet. Aug 1999;65(2):279-86. [Medline].

  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].

  18. Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. Feb 2005;115(2):391-8. [Medline].

  19. Lebet T, Chiles R, Hsu AP, Mansfield ES, Warrington JA, Puck JM. Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray. Genet Med. Aug 2008;10(8):575-85. [Medline].

  20. Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. Jan 29 2009;360(5):447-58. [Medline].

  21. Booth C, Hershfield M, Notarangelo L, et al. Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006). Clin Immunol. May 2007;123(2):139-47. [Medline].

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Further Reading

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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

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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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