[CIS-PAGID] Tough case

[PD Dr. Markus G. Seidel]

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.?
platelet Volume? WAS?
iNKT cells?
phospho-stat5? other IPEX-like disorders?
CD27?
alpha fetoprotein? AT?
ADA?
If in danger and if ferritin and sIL2R Levels inrease, I would Not  
hesitate Too Long with etoposide and discuss SCT.
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/ 

> >.

>

>

>

> 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.

>

>

> ----- 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 Immun 

> odeficiencies Unit. Hospital Universitari Vall d'Hebron.    Assistan 

> t 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

-------------- next part --------------
An HTML attachment was scrubbed...
URL: <http://seven.pairlist.net/mailman/private/pagid/attachments/20120324/85f27a57/attachment.html>