[PAGID] [SPAM?] Re: VOD/CID - Sp110

[Jack Bleesing]

Thanks John:

I had been hoping for your input. Finishing the Sp110 inquiry, any reason to think that this gene is a susceptibility gene for VOD post HSCT?

Have you considered other Sp family members. For example, Sp100 is a target autoantigen in autoimmunity affecting bile ducts (including primary biliary cirrhosis) and it's expression is affected by [viral] infections and other stimuli.

Regards,

Jack

---------------------------------------------------------------------------
Jack J.H. Bleesing, M.D., Ph.D.
Associate Professor of Pediatrics
Cincinnati Children's Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Avenue, MLC 7015
Cincinnati, OH 45229
513-636-4266 (phone)
513-636-3549 (fax)
Jack.Bleesing at CCHMC.org
http://www.cincinnatichildrens.org/immunodeficiencies/



>>> "John B. Ziegler" <j.ziegler at unsw.edu.au> 9/27/2008 3:14 AM >>>

Jack

In Sydney we have seen about 20 children with VODI often with large 
sibships. Although only a minority of the siblings has been genotyped 
we can speculate that there have been about 20 heterozygous siblings 
as well as a similar number of carrier parents, about 40 people. 
Among them there has been no phenotype. In addition there has been 
genotyping carried out on some candidate phenotype cohorts, with no 
heterozygotes identified.

That said, it seems pretty clear to us that VODI cases in Lebanese 
communities are probably going undetected.  In the Sydney Lebanese 
communities the carrier frequency appears to be about 
1:50.  Extrapolating that to the population of Lebanon we would 
expect 8 new cases a year in that country. And it could be expected 
to be seen in other expatriate Lebanese communities. It has been seen 
in both Muslim and Christian families and they don't appear to 
originate in any particular part of Lebanon. Two sp110 mutations have 
been detected in the Sydney cohort. (Other mutations have been seen 
in non-Lebanese babies in the US and Italy.)  HLH has not been seen 
to date. The immunological phenotype does resemble CVID in that there 
is usually marked hypogamma but no lymphopenia and standard T cell 
function testing is usually normal. There has occasionally been a 
SCID phenotype.

That said, it is clearly early days and I'm sure we don't know the 
full story about the clinical phenotype(s). Indeed the phenotype 
paper lamentably langusihes as a manuscript.  You can get more 
information at 
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=vodi.

Your patients sound like an interesting group, rare presentation of 
heterozygotes would have to be a possibility, or a milder phenotype 
associated with mutations with less impact on the function of sp110 
than has been seen in VODI.

Best wishes

John

.   10:40 PM 26/09/2008, you wrote:

>Good morning Folks:

>

>I was wondering if there is anybody, who would like speculate 

>whether [mono-allelic] Sp110 mutations have a clinical phenotype.

>

>The reason I am asking is that every couple of months or so, we see 

>a child (male and  - seemingly healthy - present with severe 

>hepatitis/cholangitis that is cellular based (no autoantibodies and 

>no response to "low" dose steroids). When we get involved and look 

>at the immune system (sometimes before steroids are started, as the 

>Liver Team is starting to see a pattern as well), it looks like a 

>SCID/CID immune system. Multi-gene workup of everything under the 

>CID/HLH/XLP Sun, has not shown any defect.

>

>The cellular mechanism in the liver appears to suggest a HLH-like 

>process (with increased sIL-2Ra and ferritin) with cytotoxic 

>T-cells, akin EBV-driven HLH. In the liver, we sometimes, not 

>always, find some virus (HHV-6, entervirus, adenovirus found so 

>far), suggesting that a viral infection provided the trigger. When 

>we initiate HLH therapy, things improve relatively quickly. 

>Cytopenias, especially involving platelets and neutrophils are 

>invariably present, sometimes with hemophagocytosis in the bone 

>marrow. Coagulapathy (not due to synthetic dysfunction) also.

>

>Sp110 hasn't been looked at.

>

>Regards,

>

>Jack

>

>---------------------------------------------------------------------------

>Jack J.H. Bleesing, M.D., Ph.D.

>Associate Professor of Pediatrics

>Cincinnati Children's Hospital Medical Center

>Division of Hematology/Oncology

>3333 Burnet Avenue, MLC 7015

>Cincinnati, OH 45229

>513-636-4266 (phone)

>513-636-3549 (fax)

>Jack.Bleesing at CCHMC.org 

>http://www.cincinnatichildrens.org/immunodeficiencies/ 


A/Prof John B. Ziegler
Department of Immunology and Infectious Diseases
Sydney Children's Hospital
High Street, RANDWICK NSW 2031
Australia
Tel: (02) 93821515
Fax: + 61 + 2 + 93821580
Email: j.ziegler at unsw.edu.au