[PAGID] 4 month old girl with hepatosplenomegally, lymphopenia, thrombocytopenia, hypogamma, fever, panniculitis

[Notarangelo, Luigi]

Dear Brynn:

I concur with the possibility that this is HLH (primary or secondary, hard to tell at this point). I have seen HLH in the context of severe primary immunodeficiency, including IL7R deficiency, but as pointed out the normal response to mitogens stongly argues against SCID.
You may also consider testing her for CD107a expression on the surface of in vitro activated PBMC. This test would be positive (ie, lack of CD107a expression) in primary HLH other than perforin deficiency.
One other possibility to consider is VODI, though she is not of Lebanese origin and the parents are in fact unrelated.

It will be important to see how she does on steroids, although if this HLH she may need a more robust treatment (with etoposide +/- ATG).

Best regards

Gigi


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, 9th floor, Rm 09210
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







On 5/27/10 2:02 AM, "Sabiha Anis" <sabiha_anis at hotmail.com> wrote:

Dear Dr Brynn
  I have few queries.  1. At the age of 3 & 1/2 months the IgG levels should have been more due to the presence of maternal IgG. 2. what about tests for CD40L and investigating other types of hyper IgM syndrome.  3. If the T cells are producing IFN-gamma?

Regards
Sabiha Anis
Clinical Immunologist
Sindh Institute of Urology and Transplantation
Karachi, Pakistan
________________________________
From: Brynn.Wainstein at SESIAHS.HEALTH.NSW.GOV.AU
To: pagid at list.clinimmsoc.org
Date: Thu, 27 May 2010 10:34:23 +1000
Subject: [PAGID] 4 month old girl with hepatosplenomegally, lymphopenia, thrombocytopenia, hypogamma, fever, panniculitis

Dear PAGID members.  We are looking for assistance with a 3 ½ month old girl who has presented with symptoms of,


 1.  Diffuse rash demonstrating lobular panniculitis
 2.  Fever and raised inflammatory markers
 3.  Hepatosplenomegaly with liver biopsy showing intralobular fibrosis
 4.  Anaemia and thrombocytopenia
 5.  ? adaptive immune deficiency
 6.  Hypogammaglobulinaemia (absent IgA, severely reduced IgG, normal IgM).
 7.  Lymphopenia
 8.  Failure to thrive.

The patient is the first child of non-consanguineous Caucasian Australian parents, born at term in good condition.  She is non-dysmorphic and while she initially failed to thrive, is now gaining some weight with nasogastric feeds.

Rash: She was noted within the first few days of life to have a relatively deep rash which is non-pigmented but which becomes erythematous in the context of fever.  Biopsy has since shown lobular panniculitis with predominately mononuclear infiltrate, with cells consistent with histiocytes (CD68 CD163 positive and CD1a negative).  There is no cytophagia.

Presentation with RSV infection: She presented to hospital at 2 ½ months with a respiratory infection, RSV on nasopharyngeal aspirate and relatively mild symptoms which resolved with oxygen therapy. Since that time she has had ongoing fevers and positive RSV on NPA over 3 weeks.  There was transient diarrhoea but this resolved, and she had no problems with her first round of vaccines which included live rotavirus vaccine.

Hepatosplenomegaly: She was also at admission found to have hepatosplenomegaly with ultrasound showing a homogeneous diffusely enlarged liver.  She has had a very mild transaminitis, low albumin at 19g/ L (in the context of a significant acute phase response).  Her coagulation studies are normal.  Biopsy predominately showed marked intralobular fibrosis, normal bile ducts with normal size portal tracts with a few mononuclear cells, largely histiocytic cells (CD163 and CD68 positive) but again no definite cytophagocytosis seen.  No evidence of storage disease, metabolic disorder, malignancy or infection. The liver biopsy was repeated this week to obtain a larger specimen but there is still no evidence of  cytophagocytosis or granulomata although there are numerous histiocytes.

Anaemia/ Thrombocytopenia: She also has ongoing anaemia requiring transfusion with an initially high reticulocytosis which has subsequently fallen to be just above the normal range with Hb = 70.  She is negative for red cell autoantibodies and negative for other autoimmune markers.  She has thrombocytopenia (c. 70,000) thought possibly secondary to the splenomegaly.  Bone marrow aspirate showed mild dyserythropoiesis with left shifted 'reactive' granulocytes and relatively normal megakaryocyte differentiation.

? Adaptive immune deficiency:  She has been noted to have features of possible adaptive immune deficiency with Lymphopenia 0.4 - 1.4 x 109, absent thymus, CD4 preponderance (c. 60% of lymphocytes) with CD4: CD8 ratio >4.  Relatively normal percentage of B-cells and NK cells.   She has a normal range of V* ******* **** ************* ** ***** ****** ******** ********  ****** ******* ******** ** ****  **** **** *** ****** ********** ** ******* *** *** ****** ********************* **** ******** ********* *** ******* * ****** ***** *** * ***** ****** *** *** *** **** ****** ****  *** *** ****** ********** ** *****  ***** ** ** *********** ** ******** ** ******* ****** *********** **** ****** ***** * ************ *** ****** ***** ***** *** ****** *********  **** *** *** *** ****** **** ******* ******* ****** **** ******** ***** *** *** *** * ***** ************* **** **** **** ******** *** *** ***** ******* *** * *** *******  ** **** ********** ***** ***** ****** ******** *** *** ******** ******** ********

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Dr Brynn Wainstein
Paediatric Clinical Immunologist
Staff Specialist
Sydney Children's Hospital
Tel: +61-2-9382-1515
Fax: +61-2-9382-1580



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