RAG1 deficiency may present clinically as selective IgA deficiency.
BACKGROUND
Recombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype.


OBJECTIVE
We analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies.


METHODS
We performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow.


RESULTS
Lymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function.


CONCLUSIONS
The current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.
Department of Pediatrics, National Defense Medical College, Tokorozawa, Saitama, Japan.
Tamaki
T
Kato
Elena
E
Crestani
Chikako
C
Kamae
Kenichi
K
Honma
Tomoko
T
Yokosuka
Takeshi
T
Ikegawa
Naonori
N
Nishida
Hirokazu
H
Kanegane
Taizo
T
Wada
Akihiro
A
Yachie
Osamu
O
Ohara
Tomohiro
T
Morio
Luigi D
LD
Notarangelo
Kohsuke
K
Imai
Shigeaki
S
Nonoyama
D002675:Child, Preschool; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017098:IgA Deficiency / Q000097:blood* / Q000235:genetics* / Q000276:immunology; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D060152:V(D)J Recombination
D018398:Homeodomain Proteins; D011948:Receptors, Antigen, T-Cell; C064658:RAG-1 protein