[PAGID] R: Unclear Hemophagocytosis in 14y old boy

[Reichenbach Janine]

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Dear Gigi, Stephan, and Jordan,

Thank you all very much for your most helpful input! We are very sorry to answer your prompt e-mails so late, but we will consider all of your suggestions and keep you updated on this complex patient.

All the best,
Janine 

and
Prof. Reinhard Seger

- -----Original Message-----
From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Notarangelo, Luigi
Sent: Monday, April 19, 2010 6:37 PM
To: pagid at list.clinimmsoc.org
Subject: [PAGID] R: Unclear Hemophagocytosis in 14y old boy

Dear Jeanine and Reinhard:

some leaky SCID with HLH-like features in the setting of viral infection is certainly a possibility (I saw one such case in the setting of IL7R deficiency, although here the low number of B cells would suggest to consider alternative defects). Also, maternal T cell engraftment should be ruled out. Do you have data on in vitro T cell proliferation? Analysis of T cell repertoire might also help. I would also suggest to look at CD107a expression upon in vivtro activation. Since the patient has normal perforin, looking at CD107a expression would be important to validate7ruole out other forms of primary HLH.

All the best

Gigi

Luigi D. Notarangelo
Children's Hospital Boston
Karp Building, 9th floor, room 9210
1 Blackfan Circle
Boston, MA 02115 - USA
tel: (+1)-617-919-2276
________________________________________
Da: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] per conto di Reichenbach Janine [Janine.Reichenbach at kispi.uzh.ch]
Inviato: lunedì 19 aprile 2010 10.06
A: pagid at list.clinimmsoc.org
Oggetto: [PAGID] Unclear Hemophagocytosis in 14y old boy

Dear colleagues,

We would very much appreciate any advice or ideas concerning one of our patients with hemophagocytosis syndrome, 14 years old boy of Swiss origin, no consanguinity.

First hospitalisation at the age of 9 months for viral gastroenteritis and urticaria, there is no information concerning accompanying cytopenia.

For the next years the boy suffered from exanthema (probably urticaria), reduction of general condition and fever, typically for 2-4 days, twice yearly; in each case spontaneous recovery without any intervention or medication. Again we don't have any information concerning accompanying cytopenia as there were no medical visits during this time. In the interval the boy felt completely normal.

In autumn 2008 the episodes with fever, exanthema and reduction of general condition accelerated and got worse. At each consultation at the general practitioners office cytopenias (low platelets, minimal 4 G/l, and low leucocytes, minimal 2.0 G/l, normal hemoglobin) were noticed; normal blood values in the interval. In the absence of spontaneous remission he was then treated with steroids (prednisolone 1 mg/kg/ day) for a few days with good response every time.

The exanthema looks like some kind of vasculitis, but it is transient after some hours, no urticaria. Unfortunately there was no possibility for a skin biopsy until now, because of rapid remission of the exanthema in each case.

Exams from 11/2008 in a local hospital:

Ferritin 1744 ug/l, LDH 1045 U/l, ASAT 116, Fibrinogen D-Dimers 9199 ng/ml, Triglycerides 3.85 mmol/l.
ANA, ANCA, antiDNS, Anti-MPO, Anti-PR3, Complement, Immunoglobulins and Immunelectrophoresis normal.
Normal Genetics for HIDS, TRAPS, CINCA, FCU.
Sonography Abdomen:Splenomegaly, no other pathological findings.
Normal thoracal radiograph,echocardiography, ophthalmological examination and bone marrow.

For suspicion of hemophagocytosis a treatment with
CSA (2 x 100 mg daily, 3.3 mg/kg/day) was initiated and the boy was referred to our institution:

FACS under therapy with CSA 2 x 100 mg daily showed reduced naive T lymphocytes (40 cells/ul), increased double positive T lymphocytes (16%), and reduced B lymphocytes (80 cells/ul).

EBV serology: IgG positive, IgM negative
PCR CMV, EBV, HHV-6: negative.
IgG 17.8 g/l.
HIV negative
TNF-alpha 10.10 pg/ml. sIL-2 Receptor 428.5 pg/ml.

Bone marrow: moderate phagocytosis of erythrocytes and platelets, no Leishmaniosis. Karyotype in bone marrow: 3 of 20 metaphases contained clonal aberrations, but none of these clonal aberrations is known to be characteristic of any particular type of tumour.
Normal aminoacid profile in plasma and urine
No autoantibodies against platelets and granulocytes
Analyses done in Paris, Necker:

Normal perforin dependent T lymphoctye cytotoxicity (making Munc-13-4 defect unlikely)
Normal hair (no hints for Griscelli syndrome or Chediak-Higashi syndrome)
No increase of double-negative T cells, slight elevation of FasL
Normal NKT cell phenotype
SAP and XIAP sequencing normal
No excess of apoptosis and normal T cell degranulation (making XIAP-like disease or Munc-18-2 defect unlikely)

Clinical follow-up:
He was relatively stable under therapy with 0.13 mg/kg prednisolon daily and cyclosporine 8mg/kg/d (level CSA 270 ug/l) after a first treatment with high dose immunoglobulins in 6/2009 and following slow reduction of steroids over several weeks. Since 11/2009 while still under treatment with CsA, he developed more frequent episodes of hemophagocytosis about every 3 weeks, each time with good response to treatment with IVIG.


We would be very grateful for any suggestions or ideas concerning diagnosis and potentially treatment of this tricky case.

We wonder if he could suffer from some kind of atypical SCID (considering the nearly complete absence of detectable CD31+ recent thymic emigrants and very low B cell numbers)

Best regards,
Janine Reichenbach

and Prof. Reinhard Seger

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PD Dr. med. Janine Reichenbach
Oberärztin Abteilung Immunologie/Hämatologie/KMT
Jeffrey Modell Diagnostic Center for Primary Immunodeficiencies

Universitäts-Kinderspital Zürich
Steinwiesstrasse 75
CH-8032 Zürich
Tel.: +41 (0)44-266-7341
Fax: +41 (0)44-266-7914
e-mail: janine.reichenbach at kispi.uzh.ch<mailto:janine.reichenbach at kispi.uzh.ch>


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