Mutational analysis pinpoints many types of SCID: more than 20 genetic loci are referenced in the Online Mendelian Inheritance in Man (OMIM) database. Large deletions of chromosomal material are not seen, and this limits 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 SCID.
Overall, SCID is characterized by profound abnormalities in T-cell, B-cell, 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 (see Table 1 below).
Table 1. Common Causes of SCID, Cellular Defects, and Inheritance Pattern (Open Table in a new window)
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. |
||||
SCID is most commonly due to an X-linked mutation of the gene coding for the γ chain that is common to the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. XL-SCID accounts for approximately 50% of all cases of SCID. Mutations in the intracellular tail of the common γ chain are associated with a less severe form of XL-SCID. Defective expression of the common γ chain can be detected by flow cytometry. SCID has also been described due to compound heterozygous mutations in the MTHFD1 gene. [31] Hydroxocobalamin and folate therapy provided partial immune reconstitution.
The remainder of SCID cases result from the following autosomal recessive or, less commonly, sporadic mutations:
-
ADA and PNP deficiencies
-
Mutation of the IL-7R α chain
-
IL-2 production defects
-
Mutation of JAK3
-
Null mutations in RAG1 and RAG2
-
Artemis gene mutations
-
CD45 mutations
-
Mutations of ZAP70
-
CD3γ, ε, and δ mutations
-
MHC class II deficiency caused by mutations of components of the transcription factors of MHC II, including CIITA
-
Bare lymphocyte syndrome
-
Deficiency in p56lck (a tyrosine kinase–signaling molecule in the IL-2–mediated JAK-STAT pathway)
-
Cartilage-hair hypoplasia
-
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.
-
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.
-
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. |
||||
