Diagnostic Considerations
Misdiagnosing severe combined immunodeficiency (SCID) as hypogammaglobulinemia is a common error. When patients first present with common bacterial infections such as otitis media and pneumonia, a diagnosis of agammaglobulinemia often is considered. In fact, early descriptions of SCID were termed Swiss agammaglobulinemia.
In almost all cases, flow cytometry immediately distinguishes between B-cell deficiencies and lack of mature T cells. Other immunodeficiency syndromes, particularly DiGeorge syndrome, may lack T-cell function completely and resemble SCID clinically. The nonimmunologic features of these T-cell disorders usually distinguish them.
CD40 ligand (CD154) deficiency—that is, X-linked hypogammaglobulinemia with hyper–immunoglobulin M (IgM)—may present with recurrent otitis media and Pneumocystis pneumonia, as does SCID; the former has normal populations of mature T cells, B cells, and NK cells, unlike most variants of SCID.
In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:
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Leiner disease
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Letterer-Siwe disease
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Primary immunodeficiency
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Congenital TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes simplex, or other infections) infection
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Other forms of hypogammaglobulinemia
Differential Diagnoses
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Cutaneous Manifestations of HIV Disease
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Graft Versus Host Disease
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Immunologic Aspects of DiGeorge Syndrome
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Wiskott-Aldrich Syndrome
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This patient presented with fever and paralysis of his left arm 3 months after receiving his third oral poliovirus vaccine. Past history included chronic thrush presenting in the absence of antibiotic therapy or breastfeeding at 2 months, chronic diarrhea from 4 months, and recurrent otitis media. He was at the 90th percentile for height and weight, similar to his parents. Major histocompatibility complex (MHC) class II deficiency was diagnosed by immunologic tests.
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This patient with an autosomal recessive type of severe combined immunodeficiency died of cytomegalovirus pneumonia when aged 22 months after prior infections that included recurrent otitis, pneumonia, and oral thrush. A CMV inclusion body is pictured in the upper left of the photo.
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Histologically, the thymus in severe combined immunodeficiency usually lacks Hassall corpuscles and is depleted of lymphocytes. In this photo, a Hassall corpuscle is identified to the right of center.
Tables
Genetic Disease Causing SCID |
T-Cell Defect |
B-Cell Defect |
NK-Cell Defect |
Inheritance Pattern |
Reticular dysgenesis |
Yes |
Yes |
Yes |
Autosomal recessive |
ADA deficiency |
Yes |
Yes |
Yes |
Autosomal recessive |
RAG1 and RAG2 deficiency |
Yes |
Yes |
No |
Autosomal recessive |
TCR and BCR recombination gene deficiency |
Yes |
Yes |
No |
Autosomal recessive |
Common γ chain deficiency |
Yes |
No |
Yes |
X-linked |
JAK3 deficiency |
Yes |
No |
No |
Autosomal recessive |
IL-7Ra deficiency |
Yes |
No |
No |
Autosomal recessive |
Omenn syndrome |
Yes |
No |
No |
Autosomal recessive |
ZAP-70 kinase |
CD4+ present |
No |
No |
Autosomal recessive |
CD4+ lymphopenia |
CD8+ present |
No |
No |
Autosomal recessive |
MHC II deficiency |
CD8+ present |
No |
No |
Autosomal recessive |
p56lck deficiency |
CD8+ present |
No |
No |
Autosomal recessive |
ADA = adenosine deaminase; BCR = B-cell receptor; JAK = Janus-associated kinase; MHC = major histocompatibility complex; RAG = recombination-activating gene; SCID = severe combined immunodeficiency; TCR = T-cell receptor, ZAP = ζ chain-associated protein. |
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