[PAGID] unusual SCIDs

[Aly.Mageed at devoschildrens.org]

I would like to get the groups' opinion regarding a 5 months old white male who presented at 3 months with recurrent URIs and eczematous rash. IgG was 62, IgA<8, IgM was 5, and IgE was 33.  WBC was 15,000 with 16% lymphs and 44% Eos. Flow data: 2418 lymphs, CD19= 1 cell, CD3 =1812 and CD16=585. Diagnosed as potential Bruton's and started on I g replacement and Btk genetic testing (full-gene sequencing of all 19 exons with intron-exon boundaries and UTRs) was performed and did not reveal any mutations and Btk protein was also normal by intracellular flow cytometry on monocytes. No transfusions and no sibs. 

 

Recent flow shows CD3= 5020, CD8= 2655 and CD4=1613 cells/uL with 14.41% DNT cells.  ALPS screening (despite lack of classic ALPS presentation) revealed only 0.5% of the DNT cells expressed the alpha-beta TCR (were also B220 negative).  The remaining DNT cells were negative for ab TCR, and may presumably be gd+ T cells.  Mitogen stim showed only 2% PHA, 40% PWM and 1% ConA relative to the normal control.  TRECs were undetectable.  CD4 RTE (CD4+CD31+CD45RA+) was 0.2% (only 3 cells/uL).  Next to zero naïve CD45RA+ T cells and the majority of the CD4 T cells express CD45RO (~99%).  The CD8 RTE (CD8+CD103+CD62L+CD45RO-) showed an apparent increase due to the overall CD8 lymphocytosis, however, again on examination of the CD45RA gate, there were hardly any CD45RA+ CD8 T cells present, the majority were CD45RO+ (>99%).  Therefore, in reality, CD8 RTE is also absent.  

 

Now, he is in house with staph bactremia. Thriving at 8 Kg with some diarrhea once started on Bactrim a month ago. Rash has its ups and downs with increasing erythroderma and what looks like age/sunspots  that are increasing in #, which will be biopsied. Has mild splenomegaly and some inguinal and cervical adenopathy. IgG is 522 (gets IG which will be increased) and IgE is 14, Eos = 13%. No cytopenias. XX/XY probe surprisingly show all male XY cells with no evidence of maternal engraftment. 

 

It is unclear as to how there can be such a substantial population of T cells with a memory phenotype (CD45RO+) in the blood of this infant along with a sizable population of DNT cells that are ab TCR-negative, if there is no external source, such as maternal engraftment, i.e. where are these cells originating from, especially since thymic output appears to be non-existent.  There certainly seems to be a reasonable amount of data in the literature to support extrathymic maturation and TCR rearrangement in the human gut (both gd and ab TCR+) but the question remains as to whether that is indeed what is happening in this patient.  We are trying to look at RAG1/2, Artemis and JAK3 but so far unsuccessful as he is Medicaid and social worker is still working on these issues. HLA is pending for UCB/MUD search. Is this Omenn's ? Any further testing - would gamma delta rearrangement analysis (clonality assessment), TCR V beta analysis to look for oligoclonal populations be worthwhile? Radiation sensitivity pathway? Additional thoughts??"

Thanks 

 

Aly Mageed, MD, MBA
Division Chief, Pediatric Blood & Marrow Transplant Program
Director, Stem Cell Engineering Laboratory
Helen DeVos Children's Hospital, Spectrum Health
Associate Professor of Pediatrics, Michigan State University
Grand Rapids, MI 
(616)-391-3962
aly.mageed at spectrum-health.org <mailto:aly.mageed at spectrum-health.org> 
 
 
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