[CIS-PAGID] Tough case

[Pere Soler Palacin]

Dear Markus, thanks for your comments. See answers below. 




Dear Pere, dies the Boy have any other viral infections than the noro virus, does He suffer from chronic diarrhea/enteropathy, thrive normally? What about other autoantibodies? endocrinology normal and celiac d.?  No other viral infections, no chronic diarrhea and normal growth. Autoantibodies tested and negative except for antiperoxidase slightly increased (but not significant to our endocrinologists) No intestinal biopsy to study celiac disease and antibodies not tested due to hypogammaglobulinemia 
platelet  Volume? WAS?  No thrombocytopenia and normal platelet volume. 
iNKT cells? 
phospho-stat5? other IPEX-like disorders? Normal stature. FOXP3 and CD25 normal. Other tests? 
CD27? not sure, i'll ask my colleagues from the lab. alpha fetoprotein? AT? not tested 
ADA? not tested 

If in danger and if ferritin and sIL2R Levels inrease, I would Not hesitate Too Long with etoposide and discuss SCT. That is our idea for the next week. 
yours, Markus Seidel   
markus.seidel at medunigraz.at   

Am 24.03.2012 um 14:03 schrieb Pere Soler Palacin < psoler at vhebron.net >: 








Thanks Stephan for your comments. See answers below: 


IgE: between 300 and 400 UI/L 
Uric acid - PNP: uric acid normal; purine metabolism not studied yet. 
Radiosensitivity (even though normal B cells)? Not tested. It's not easy to do it in our centre. 
Telomers? Not done, but skin biopsy was not consistent with DC. 
What does the bone marrow say? global hypocellularity without signs of myelodysplasia and some signs of hemophagocytosis. Cytogenetics were normal. 
Langerhans cell histiocytosis ruled out for sure? Yes. 

Best wishes, ST 


----- Originalnachricht ----- 
Von: "Notarangelo, Luigi" [Luigi.Notarangelo at childrens.harvard.edu] 
Gesendet: 23.03.2012 19:47 GMT 
An: " pagid at list.clinimmsoc.org " < pagid at list.clinimmsoc.org > 
Betreff: Re: [CIS-PAGID] Tough case 



I would look for T cell oligoclonality. The normal number of B cells (pre-rituximab) would argue against RAGs, however we have seen a family with Tlo B+ NK+ and hypergammaglobulinbemia (!) who presented with just autoimmunity and had disease-causing mutations in RAG2. 
Can you retrieve Guthrie card and check for TRECs at birth? 

Luigi D. Notarangelo, M.D. 
Jeffrey Modell Chair of Pediatric Immunology Research in Boston 
Director, Research and Molecular Diagnosis Program on Primary Immunodeficiencies 
Division of Immunology, Children's Hospital 
Professor of Pediatrics and Pathology, Harvard Medical School 
Karp Building, 10th floor, Rm 10217 
1 Blackfan Circle 
Boston, MA 02115 
USA 

(tel) (617)-919-2276 
(fax) (617)-730-0709 


Secretary: Luisa Raleza 
email: luisa.raleza at childrens.harvard.edu 


From: "Bleesing, Jacob" <Jack.Bleesing at cchmc.org< mailto:Jack.Bleesing at cchmc.org >> 
Reply-To: <pagid at list.clinimmsoc.org< mailto:pagid at list.clinimmsoc.org >> 
Date: Fri, 23 Mar 2012 19:14:16 +0000 
To: "pagid at list.clinimmsoc.org< mailto:pagid at list.clinimmsoc.org >" <pagid at list.clinimmsoc.org< mailto:pagid at list.clinimmsoc.org >> 
Subject: Re: [CIS-PAGID] Tough case 

Can you elaborate a bit more on the T-cell proliferation studies, was patient on immunosuppressives, etc. Studies done at presentation? 

If I read it correctly, it seems a bit odd that PHA response (with or without adding IL-2) works fine, but PMA/Ionomycin is mildly decreased. IL-2 seems to help in vitro. 

Thanks 

Jack 



________________________________ 
From: pagid-bounces at list.clinimmsoc.org< mailto:pagid-bounces at list.clinimmsoc.org > [pagid-bounces at list.clinimmsoc.org< mailto:pagid-bounces at list.clinimmsoc.org >] on behalf of Pere Soler Palacin [psoler at vhebron.net< mailto:psoler at vhebron.net >] 
Sent: Friday, March 23, 2012 3:05 PM 
To: pagid at list.clinimmsoc.org< mailto:pagid at list.clinimmsoc.org > 
Subject: Re: [CIS-PAGID] Tough case 


Dear Joao, Rafael and Tony, don't you think that hypergammaglobulinemia of all three isotypes at the very beginning would rule leaky-SCID out? 



Pere. 


Pere Soler Palacín, MD, PhD. 
Pediatric Infectious Diseases and Immunodeficiencies Unit. Hospital Universitari Vall d'Hebron. 
Assistant Professor. Universitat Autònoma de Barcelona. 
Passeig de la Vall d'Hebron 119-129. 
08035 Barcelona. Spain. 
Tel: 0034934893140. Fax: 0034934893039. 
E-mail: psoler at vhebron.net< mailto:psoler at vhebron.net >; 34660psp at comb.cat< mailto:34660psp at comb.cat >. Web: www.upiip.com< http://www.upiip.com/ >. 



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----- Mensaje original ----- 
De: "Oliveira Filho, Joao (NIH/CC/DLM) [E]" <oliveirajb at cc.nih.gov< mailto:oliveirajb at cc.nih.gov >> 
Para: pagid at list.clinimmsoc.org< mailto:pagid at list.clinimmsoc.org > 
Enviados: Viernes, 23 de Marzo 2012 19:57:53 
Asunto: Re: [CIS-PAGID] Tough case 

I'd go straight to RAG1/2 sequencing: skin, mild lymphopenia, no naive lymphs.  If neg would look for other genes involved in leaky SCID with Ommen's. 
Bosco 


Joao Bosco Oliveira, MD PhD 
Head, Human Disorders of Lymphocyte Homeostasis Unit 
Assistant Chief, Immunology Service 
Department of Laboratory Medicine 
NIH Clinical Center 
Building 10, Room 2C410 
10 Center Drive 
Bethesda, MD 20892 
Tel: 301 594-1971 
Fax: 301 402-1884 






On 3/23/12 2:16 PM, "Pere Soler Palacin" <psoler at vhebron.net< mailto:psoler at vhebron.net >> wrote: 


Dear colleagues, we'd really appreciate your thoughts about this tough case we are currently facing since we are in an impasse and the patient is severely ill. 



Fifteen month-old boy, with severe skin involvement, spleen and liver enlargement and hemolytic anemia that presents recurrent episodes compatible with macrophage activation syndrome. 
Clinical manifestations began at the age of 9 months with haemolytic anemia (positive direct Coombs test) and splenomegaly. Immunoglobulin plasma levels were increase. (Ig G above 1000 mg/dL and both IgA and IgM above 200 mg/dl) and lymphocyte subsets analysis yielded mild lymphopenia (1280 /mm3. Lymphocyte subpopulations at the onset of the manifestations, CD3+: 35% (448 /mm3), CD4+:22% (281.6 /mm3); CD8+: CD8+: 13%, (140.8 /mm3), CD19+: 537.6 /mm3, CD156+16+: 294.4 /mm3. 

Corticosteroid therapy and high dose IVIG were started ant that point, and since anemia was refractory to these treatments, the patient was put on rituximab (5 doses). The patient needed repeated (not irradiated) blood transfusions. 
At 11 months of age and because of the persistence of anemia, he was switched to cyclosporine and mycophenolate mofetil afterwards since ALPS was suspected (although DNT cells biological markers were absent). Few days later fever, pancytopenia and severe rash occurred and MMF was changed to sirolimus without significant clinical improvement. Bone marrow aspirate was performed and informed to be normal. 
The patient was sent to our centre at that point (14 mo). Physical examination showed hepatosplenomegaly, generalized lymphadenopathy, severe erytroderma with scaly skin that sheds off and pruritus (see figure). 
At that moment, we considered five diagnostic options: 
-          Histiocytosis: skin biopsy ruled it out. 
-          Cutaneous T-cell lymphoma (Sezary): skin biopsy ruled it out and it's only seen in adult patients. 
-          ALPS/DALD: Neither DNT cell nor biomarkers were found. No mutations in TNFRSF6 (FAS) or KRAS genes. No DNT in lymph node biopsy. 
-          Hemophagocytic lymphohistiocytosis (HLH): initial NK cells cytotixicity and degranulation assays were abnormal and the patient presented elevated ferritin (90.000 ng/mL), tryglicerides (400 mg/dl) levels and hypofibrinogenemia. CD25s was 1700. BM aspirate and lymph node biopsy showed some signs of hemophagocytosis. Nevertheless, when immunosuppressant drugs were tapered enough, NK cyto and degranulation assays return to normal. Perforin expression was normal in CD8 and NK cells. Skin was not compatible with HLH. 
     -      Leaky-SCID with Omenn or GVHD (maternal or post-transfusional): 
-          Lymphocyte subpopulations, data from our center at age 11 months: CD3: 96% (3.973X109/L), CD4: 80% (3.296X109/L), CD8: 16% (0.668X109/L), 0% B cells (CD19+), 1% NK cells CD56+16+) 
-          T cell population mostly activated expressing HLA-DR CD4: 58% and  CD8: 87%. 
-          90% of CD3 T cells with effector memory pheenotype (CD45RO+CCR7-) 
-          TCR ab/gd phenotype was evaluated 93.3%/5.3%. 
-          CD3 and CD2 expression did not show significant differences 
-          Absence of B cells (secondary to RTX infusion). 
-          NK cells 1.6% (0.066X109/L), 
      -      Proliferation to PHA, PHA+IL2, IL2 and anti-CD3+IL2 was normal, PMA+ionomic slightly decreased and anti-CD3 response severely depressed. 

-          Hypogammaglobulinemia was thought to be secondary to RTX too. Proliferation assays were significantly low and TCR was oligoclonally expressed. Chimerism assays did not show maternal or transfusional cells and skin biopsy was not compatible with OS. Only port-a-cath infection due to P. aeruginosa and diarrhoea due to Norovirus were demonstrated as significant infections. Visceral leishmaniasis has been ruled out. 

We tried to tapper all immunosuppressant drugs to better evaluate his "own" immunological status. The patient remained hematologically stable (only needing weekly IVIG to maintain normal Hb levels) but skin progressively worsened to severe and became the main clinical problem in our patient. 
Skin biopsy showed a psoriatic dermatitis and hair was normal when observed at optic microscope. 
The patient has presented two new episodes of fever, increase of spleen and liver size, cytopenias and skin involvement and we decided to start HLH-2004 protocol (VP-16 not yet) and the patient only improved transiently. 

Since, psoriatic dermatitis is described to be associated to IPEX and IPEX-like syndrome we analyzed FOXP3 and CD25 and were found to be normal. Inborn metabolic disorders) have been properly ruled out. 


Thanks in advance, 



Pere. 
Pere Soler Palacín, MD, PhD. Pediatric Infectious Diseases and Immunodeficiencies Unit. Hospital Universitari Vall d'Hebron.    Assistant Professor. Universitat Autònoma de Barcelona. 
Passeig de la Vall d'Hebron 119-129. 
08035 Barcelona. Spain. 
Tel: 0034934893140. Fax: 0034934893039. 
E-mail: psoler at vhebron.net< mailto:psoler at vhebron.net > < mailto:psoler at vhebron.net > ; 34660psp at comb.cat< mailto:34660psp at comb.cat > < mailto:34660psp at comb.cat > . Web: www.upiip.com < http://www.upiip.com/ > . 


No imprimir aquest correu ajudarà a preservar el medi ambient. 
Si vostè no és el destinatari del missatge, o l'ha rebut per error, si us plau notifiqui-ho al remitent i destrueixi el missatge amb tot el seu contingut. Està prohibida la distribució no autoritzada del contingut d'aquest missatge. 

No imprimir este correo ayudará a preservar el medio ambiente. 
Si usted no es el destinatario del mensaje, o lo ha recibido por error, notifíquelo por favor al remitente y destruya el mensaje con todo su contenido. Está prohibida la distribución no autorizada del contenido de este mensaje. 




-- 
Dra. A.Martín Nalda 
Unidad de Patología Infecciosa e Inmunodeficiencias de Pediatría 
HMI Vall d´Hebron 
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