[CIS-PAGID] Tough case

[Nacho Gonzalez]

Dear Pere,

I agree with previous comments concerning Omenn syndrome and leaky scid.In
any case (hlh or leaky scid) this patient BMT should be strongly
considered.For foci analysis you can contact in Madrid with my colleague MJ
Recio at the Complutense University (email  majoreho at med.ucm.es ).For
telomere assays you can contact with the only people (as far as I know
works in this field in Spain,Rosario Perona  rperona at iib.uam.es)
I expect this may help
Luis Ignacio Gonzalez Granado
Immunodeficiencies Unit
Madrid.Spain
El 24/03/2012 14:03, "Pere Soler Palacin" <psoler at vhebron.net> escribió:


> 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.

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>

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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.

>

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> Si usted no es el destinatario del mensaje, o lo ha recibido por error,

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>

>

>

>

> --

> Dra. A.Martín Nalda

> Unidad de Patología Infecciosa e Inmunodeficiencias de Pediatría

> HMI Vall d´Hebron

>

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