[CIS PIDD] [cis-pidd] Autoimmunity

Tue Jul 19 20:13:48 EDT 2016

Thanks for your comments Rob!  I was hoping that the exome that was run
would not miss a WAS mutation.  I certainly was very concerned about WAS
originally as well which is why we also looked at WASp expression. 

Dave

>>> "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org> 7/14/2016 8:00 AM >>>

I would sequence WASp if that hasn’t been done, including the introns
or at least intron-exon junctions. Depending on the antibody used and
the mutation, one can see normal expression of WASp with decreased
function. Some additional clues that could indicate that this phenotype
might be related to WASp deficiency and that you may already have in the
clinical records include high IgA/low IgM, lo MPV (although this can be
normal in WAS), inappropriately low or normal  immature platelet
fraction in the setting or thrombocytopenia (Candotti recently published
a paper looking at a formula combining IPF and platelet count to
differentiate WAS and ITP, (75 x IPF + plts < 500 suggests WAS, with
plts expressed in 100,000’s/mcL. This formula may identify
hypoproliferative thrombocytopenia in general, not just WASp Frontiers
in pediatrics, 2015), Platelet aggregometry showing storage pool defect
(absence of a 2nd wave of aggregation to epinephrine with otherwise
normal aggregometry) and low numbers of dense bodies, although higher
than seen in HPS (about 1-3 db’s/platelet). All of this data could be
supportive, but would only indicate that sequencing WASp would be more
likely to be relevant. Much of this platelet data ought to already be
available based on your mention of a platelet functional defect and
platelet EM. MPV and IPF can come off the same blood used for CBC, and
may have been already done but not reported if a sysmex hematology
analyzer was used.

A functional WAS assay could be done, or a Western looking for
truncated protein, but it is probably easier to sequence WASp directly,
and those assays would not be standardized in any case.

Would consider anti-TNF therapy for Crohn’s-like disease, but would
defer to GI.

Can discuss off line if you would like.
-Rob

--
Rob Sokolic, MD
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Center for Biologics Evaluation and Research
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From: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org] 
Sent: Thursday, July 14, 2016 3:41 AM
To: CIS-PIDD
Subject: Re:[cis-pidd] Autoimmunity

Dear Colleagues,

I have another young man that would benefit from additional
thoughts......

I have a 17 year old young man that came to me with a history of
autism, platelet dysfunction, and a diagnosis of CVID.  No issues with
lymphadenopathy or organomegaly. He does have significant autoimmunity. 
His mother also suffers from autoimmunity.  Notably, he has had Graves
disease.  He has detectable autoantibodies to thyroid peroxidase and
thyroglobulin.  He has a positive DAT, but no clinically significant
hemolysis.  He also has some mild thrombocytopenia.  He also has had
biopsy evidence of small and large bowel inflammation with granuloma
formation.  More recently, he has developed peri-anal fistulas that have
been problematic.   He has been diagnosed with a "Crohn's-like" issue.  
No immunomodulatory therapy has been provided.  I have tried some
platelet support to see if it would help with his peri-anal fistula with
respect to healing.  It helped for a short while, but now there is
worsening.  

He has remained on immunoglobulin support for many years.  On
immunoglobulin support his immunoglobulin levels are normal including a
IgE level (not elevated).  His lymphocyte immunophenotyping is
relatively unremarkable. Absolute numbers are as follows:  CD3 682,  CD4
460, CD8 207, CD19 140, CD45RA 322, and CD45RO 183. Memory B cells and
class switched memory B cells are slightly diminished at 12 and 5;
respectively.  Absolute numbers of naive B cells are fine.    

He has had some genetic testing done including testing for
mitochondrial issues and Fragile X.  A microarray was done -  a 150 Kb
loss was noted on the long arm of chromosome #2 - thought to be likely
benign. Exome analysis was done 2 years ago without any variants of
clinical relevance at a outside center.  I looked for a few things
functionally -  his DHR was normal.  WAS protein expression was normal. 
FOXP3 analysis was normal.  IL-10 pathway analysis was unremarkable.  I
did platelet EM to look for evidence of HPS - normal.  

I welcome any suggestions for additional targeted genetic or functional
analysis.  I was also considering additional immunomodulatory therapy -
focusing on his fistualizing issues (? rituximab + azathioprine or other
agents such as ? sirolimus).  Any suggestions would be welcome as well
in this arena.

Thanks as always,

Dave Buchbinder, MD

CHOC Children's Hospital 

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