[CIS-PAGID] Tough case

[Pere Soler Palacin]

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% (3.973X10 9 /L), CD4: 80% (3.296X10 9 /L), CD8: 16% (0.668X10 9 /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% (0.066X10 9 /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 dem onstrated as significant infections. Visceral l eishmaniasis 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 ; 34660psp at comb.cat . Web: www.upiip.com . 
  

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