[CIS PIDD] Recurrent HLH like episodes with persistentsplenomegaly

[Joshi, Avni Y., M.D.]

Hello Markus,
Thank you for your comments.
He is EBV seronegative and his B cell count is 56 ( normal range for his
age:110-570cells/ul).
He has good vaccine responses to TT and DT.
NK cytotoxicity ,PRF and Granzyme expression is normal.
As suggest by Gigi and Ashish, we did perform the TCR V beta
spectratyping and degranulation assays and both are normal.
PHA mitogen proliferative responses and anti-CD3 are also normal.
 
So the only question remaining is of ALPS and we are tapering him off
the sirolimus and prednisone, to be in a better position to perform the
ALPS screen, apoptosis assay and Fas sequencing on sorted DNTs for
possible Somatic Fas mutation.
I agree, at this point in time, I do not see any indication to discuss
BMT.
 
Thank you all for your insights,
Avni

________________________________

From: pagid-bounces at list.clinimmsoc.org
[mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Seidel Markus
Sent: Sunday, August 05, 2012 7:45 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS PIDD] Recurrent HLH like episodes with
persistentsplenomegaly



Dear Avni,

Did EBV play a role in these episodes? Did the boy develop ENB1 Abs? How
low are the B cells, how are the B-subsets? Vaccination antibodies?

Is the T Vb repertoire skewed?

Range of iNKT cells, NK cytotoxicity, aptopostis assays?

Do you know about the CD27 expression? ITK deficiency possible? 

Has LCH, although unlikely, been excluded?

Also unlikely, but what about granulomatous disease, neutrophil function
tests (I know a boy who after recurrent massive lymphadenopathies, often
responding to antibiotics, sometimes to steroids, with chronic
splenomegaly who was identified as X-CGD at 14yrs of age; admittedly, he
had had Crohn's like disease as a toddler and [borderline] normal
neutrophil tests previously). And I am sure you measured ACE and
obviously excluded sarcoidosis (histology), yersinia pestis or other
infections (would not improve under steroids),...?

In my opinion, it appears a little too "early" to discuss BMT,

Thanks for an update,

Sincerely, Markus Seidel

 

Markus G. Seidel, M.D., Assoc.Prof.

Consultant| Dept.of Pediatric Hematology-Oncology | Univ.Clinics of
Pediatric and Adolescent Medicine | Auenbruggerpl. 34/2 | A-8036 Graz |
Austria | T. 0043 316 385 80215| F. 0043 316 385 13450

Coordinator of the Working Group for Pediatric Immunology of the
Austrian Society of Pediatrics and Adolescent Medicine

 

 

________________________________

Von: pagid-bounces at list.clinimmsoc.org
[mailto:pagid-bounces at list.clinimmsoc.org] Im Auftrag von Joshi, Avni
Y., M.D.
Gesendet: Donnerstag, 19. Juli 2012 19:51
An: pagid at list.clinimmsoc.org
Cc: Khan, Shakila P., M.D.
Betreff: [CIS PIDD] Recurrent HLH like episodes with persistent
splenomegaly

 

Dear Colleagues, 

We would appreciate input on this child who have come all the way from
India paying out of pocket for a second opinion about the possibility
for BMT:

This is a 12 yr old  Asian Indian boy ( non consanguineous) who has a
history of recurrent episodes of lymphadenopathy and cytopenias.

He started off about 4 yrs. ago , with an episode of high grade fever,
LAD and splenomegaly. Infectious w/up in India was negative, yet was
treated for typhoid fever. Things were quiescent for the next two years
except that his spleen was still palpable.  Dad, being a surgeon, would
examine him, but he was symptomatically doing well. In 2008, he
developed some skin lesions  was seen by a dermatologist and were
thought to be erythema nodosum and was given prednisone for 20 mg per
day.  The spleen size improved significantly while being on prednisone,
but his skin lesions did not improve.  Prednisolone was stopped after a
month's time, and his skin lesions slowly improved in the next two to
three months' time. He had another recurrence of these episodes of
high-grade fever with cytopenia, splenomegaly, and lymphadenopathy when
he was seen by a hematologist , who diagnosed him to have ALPS.  His
double-negative T-cells were in the normal range.  Bone marrow biopsy
was normal and was negative for lymphoma, and his lymph node biopsy
samples were sent to Oxford which showed there were no B-cells, but
there was increased T cell numbers, mostly CD8s.Coombs
testing/antiplatelet antibody testing not done.

High dose steroids did improve his symptoms, and he did well for a
year's time until last year when he had recurrence of his splenomegaly,
with his spleen reaching into his right iliac fossa.  He was seen by an
immunologist and his double-negative T-cells were borderline high.  He
was again diagnosed with ALPS, and genetic testing for FAS, Fas-L, and
Caspase-8 was sent to Japan and was negative.  He was initially started
on mycophenolate mofetil which did not improve his symptomatology.  He
was then switched to sirolimus. His counts drop on sirolimus monotherapy
but stabilize when Prednisolone was added. He developed varicella on the
combination in Dec 2011.  

More recently, in April 2012 he was diagnosed with neuropathy.  EMG is
suggestive of sensorimotor peripheral neuropathy with features that
would suggest a combination of demyelination and axonal loss.   He had
recurrence of the skin lesions which were biopsied and showed evidence
of occasional histiocytes.

His bone marrow biopsy has shown evidence of hemophagocytosis on and off
during these events. 
Only significant F/H is a maternal cousin has sensorineural hearing
loss. 
He is currently on 20mg/d of prednisolone ( close to a year now)and
3mg/d of Sirolimus. 

Labs in US: 
CBC: mild lymphopenia and thrombocytopenia, no eosinophilia. 
TBNK: T ,B and NK cell lymphopenia 
ALPS screen: Negative 
sIL-2: 1010 ( Normal: 45-1105 U/ml) 
NK subsets :Normal and robust expression of perforin and Gran A/ Gran B 
SAP and XIAP expression: Normal 
Bone/lymphnode/Skin Bx read here: essentially normal, occasion
expression of CD1a and S-100 positive Langerhans cells, relative paucity
of B cells. No granulomas.(The Bx have been on at least 20mg/d of
Prednisolone)

Immunoglobulins:A,M, G and E: Normal, never been on IGIV. 
Recent Thymic Emigrant (CD4RTE): Modestly decreased. 
Vit B12: Normal 
Ferritin: Normal 

Would you consider leaky SCID, hypomorphic RAG mutation? 
Due to financial constrains, we have not performed any genetic testing
yet. 
Dad is 9/10 match . 
I'd appreciate any thoughts, recommendations or insights. 
Would you recommend BMT? 

Thank you so much for your time, 
Avni 

 

Avni Y Joshi, MD, MSc
Assistant Professor of Pediatrics and Medicine
Pediatric and Adult Allergy / Immunology
Cellular and Molecular Immunology Laboratory
Pager: 507-293-5387
Secretary: 507-538-0127
Fax: 507-284-0727
E-mail: joshi.avni at mayo.edu
_______________________________
Mayo Clinic
200 First Street SW
Rochester, MN 55905
www.mayoclinic.org <file:///\\www.mayoclinic.org\>  

 

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