[PAGID] R: WAS with normal mpv

[Rohan Ameratunga]

Dear Colleagues,

Thanks for the helpful comments.  The platelets were sized by different methods on over 20 occasions (!) before my group was approached to sequence the WAS gene.

Thanks for the comment about "ITP" in WAS but the interesting observation was the consistency in both brothers.  

If needed for diagnostic purposes in the future, we would like to undertake detailed studies of the bone marrow.  We should be able to distinguish the younger child's megakaryocytes from his mother's by FISH.  EM studies of morphology are planned.

I suspect however a future publication will be a descriptive observation rather than being able to conclusively identify the mechanism of small platelets in WAS.  The murine WAS literature has not been helpful, although ectopic shedding of platelets may be the mechanism of thromobytopenia.

Best regards

Rohan



-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org on behalf of Jack Bleesing
Sent: Tue 7/8/2008 4:54 AM
To: pagid at list.clinimmsoc.org
Cc: Lochie Teague
Subject: Re: [PAGID] R:  WAS with normal mpv
 
Good point.

Furthermore, we have seen normal or near-normal MPV values in WAS patients with associated autoimmune platelet destruction (a relatively common feature in WAS). Once/if the ITP component is treated, the MPV tends to decrease.

Approaching this from the "ITP" side (not all too infrequent the initial diagnosis in WAS patients);  peripheral platelet destruction without compensatory increases in MPV might be considered unusual (inappropriate) and warrent WAS consideration.

J

---------------------------------------------------------------------------
Jack J.H. Bleesing, M.D., Ph.D.
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/



>>> "Torgerson, Troy" <troy.torgerson at seattlechildrens.org> 7/7/2008 12:02 PM >>>

The other thought I might add to Gigi's comments about evaluating
platelet size is that if the MPV is being calculated by one of the
automated CBC instruments commonly used in clinical labs, you may not be
getting an accurate value.  Because of the way they have the cutoff set,
the instrument/software used here in our clinical lab will discard
really small platelets as being debris and therefore not include them in
the MPV calculation so many of our WAS patients have "normal" or near
normal MPV's according to that instrument.  If we have the lab do a
manual differential, the low MPV becomes evident. 

Best,

TT 

Troy R. Torgerson MD PhD
Assistant Professor, Pediatric Immunology/Rheumatology
Co-Director Immunodeficiency Molecular Diagnostics Laboratory
University of Washington and Children's Hospital
1900 9th Avenue
Seattle, WA  98101-1304
 
Tel (206) 987-7450
Fax (206) 987-7310
-----Original Message-----
From: pagid-bounces at list.clinimmsoc.org 
[mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Notarangelo,
Luigi
Sent: Monday, July 07, 2008 1:01 AM
To: pagid at list.clinimmsoc.org; pagid at list.clinimmsoc.org 
Cc: Lochie Teague
Subject: [PAGID] R: WAS with normal mpv

Dear Rohan:

I apologize for the delay (you had contacted me directly, but I was not
in town).
We have identified the E133K mutation in three patients, all of which
had classical WAS. However two of these patients were referred to us
from other colleagues, and there were no data on the MPV. The third
patient is a child I took care of. He also had classical WAS (very
severe thrombocytopenia, very severe eczema and multiple and severe
infections) and died early in life of CNS hemorrhage (he was not
transplanted because of lack of a suitable related or unrelated donor).
His MPV was consistently very low (4 fL). One key consideration is that
MPV is very difficult to evaluate. False low MPV values are common in
patients with severe thrombocytopenia; on the other hand, aggregates may
lead to false-normal (or near-normal) MPV values in WAS. At the time I
saw the child I mentioned, we did not perform a thorough analysis of the
platelets, so the values I gave are the ones in the medical records.
Importantly, we could not perform WASP protein expression analysis on
his platelets or fresh blood cells, because he died prior to cloning of
the WASP gene.

Best regards

Gigi


Luigi Notarangelo
Professor of Pediatrics, Harvard Medical School
Division of Immunology, Children's Hospital
Karp Research Building, 9th floor, Rm 09210
1 Blackfan Circle
Boston, MA 02115
USA
tel: 617-9192277



-----Messaggio originale-----
Da: pagid-bounces at list.clinimmsoc.org per conto di Rohan Ameratunga
Inviato: dom 7/6/2008 7:23
A: pagid at list.clinimmsoc.org 
Cc: Lochie Teague
Oggetto: Re: [PAGID] WAS with normal mpv
 
Dear Colleagues,

 

We would like your advice on two brothers with WAS, one aged 3 yrs and
other 18 months.  The older child presented with severe thrombocytopenia
(platelets <10) and severe eczema.  He had otitis media.  No visceral/
deep seated infections.  The younger boy was born with similar symptoms
and had one intracerebral bleed.

 

After discussion we performed mutation analysis and both have an E133K
mutation, suggesting a severe WAS phenotype.

 

What is very unusual is that both have had persistently normal mpvs
(7.5-8 FL)

 

Both have been transplanted.  The older one had a MUD while the younger
one had his mother's marrow.

 

Patients with mutations of the CDC42 region of WASP can have normal mpvs
but the phenotype is completely different from classical WAS. 

 

We would like to further investigate why these WAS children have a
normal mpv.  Our review of the literature has not explained why the mpv
is so low in WAS.  

We have considered a reversion event but this would be unlikely in two
individuals.

 

I have already discussed these children with several former North
American colleagues.  Thanks for their responses.  

 

Any other thoughts would be very much appreciated.

 

I am copying this to the family's peds haematologist in case any other
clinical details are needed. 

 

Best regards

 

Rohan Ameratunga

Adult and paediatric immunologist

Auckland

NEW ZEALAND

	





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