[CIS PIDD] [cis-pidd] Autoimmunity

Thu Jul 14 11:00:55 EDT 2016

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
Medical Officer
Office of Cellular, Tissue and Gene Therapies
Center for Biologics Evaluation and Research
Food and Drug Administration
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Robert.Sokolic at fda.hhs.gov<mailto:Robert.Sokolic at fda.hhs.gov>
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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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