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

[Dimitriades, Victoria R.]

Brynn,
 
These symptoms sound similar to a late presentation of neonatal lupus erythematosus (rash, cytopenias, hepatosplenomegaly). Has the child been tested for autoantibodies (dsDNA, SSA, SSB)? And, for that matter, has the mother?
 
Thank you for the interesting case-
Victoria
 
 
Victoria Dimitriades, MD
Assistant Professor of Pediatrics
Division of Allergy/Immunology and Rheumatology
Louisiana State University Health Sciences Center
Children's Hospital of New Orleans
(504) 896-9589 (A/I)
(504) 896-9385 (Rheum)

________________________________

From: pagid-bounces at list.clinimmsoc.org on behalf of Brynn Wainstein
Sent: Wed 5/26/2010 7:34 PM
To: 'pagid at list.clinimmsoc.org'
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 

a.	Hypogammaglobulinaemia (absent IgA, severely reduced IgG, normal IgM).  
b.	Lymphopenia 

6.	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 Vb subsets with preponderance of naïve CD45RA positive T-cells.  Normal mitogen response to PHA.  Even with the normal percentage of B-cells she has marked Hypogammaglobulinemia with severely decreased IgG (0.7g/L - normal range 3.0 - 6.0), absent IgA and IgE with normal IgM.  She has normal expression of CD40.  There is no proteinuria or evidence of protein losing enteropathy with normal alpha 1 anti-trypsin and normal upper bowel and rectal biopsies.  Both ADA and PNP levels were normal, however levels were measured after she had had 3 blood transfusions. They have been repeated and are still normal. AFP = 112 (0-77).  NK cell functional assay shows normal function and are awaiting perforin testing.   
 
? Infectious predisposition: In terms of infections to date she has had 1 episode of transient oral thrush, has cleared the vaccine associated rotavirus, and has persistence of RSV on NPA with resolution of symptoms.   Infectious screen has been negative for Adenovirus, HSV, EBV, Enterovirus, HHV6, Parvovirus, CMV and VZV on a variety of specimens including liver, Norovirus, Rotavirus, Astrovirus, Cryptosporidium, Yersinia, Salmonella, shigella,  campylobacter, aeromonas and Giardia on stool.  HIV is negative, as are PCP stains on liver while there is no evidence to date for the presence of Tb.  
 
Inflammatory process + ? haemophagocytosis:   She has continued to have temperatures several times per day to > 38 - 40 degrees with CRP = 203, ESR = 14, and intermittent mild neutrophilia.  Her Ferritin is markedly elevated = 1228, LDH = 632, with borderline raised Triglicerides = 2.5 (<2.0).  Some histiocytic cells (CD163 and CD68 positive) in liver but no cytophagocytosis in liver or bone marrow. Her serum ACE level is elevated at 122 nM/ml/min.
 
Metabolic disease: Our metabolic team has been involved and is nearer the end of a negative screen with their main remaining diagnosis being Farber's disease for which testing is pending.         
 
Conclusion: While the hypogammaglobulinaemia cannot currently be explained in terms of antibody loss, in the context of the current pattern it is hard to think of a PID which could underlie all of this.  As a girl with extremely early onset of symptoms and normal CD40 we felt a hyper IgM variant is unlikely.  The normal PHA goes strongly against a combined PID.  We remain very concerned with the possibility of a haemophagocytic syndrome, either primary or secondary but are a loss to explain the association of this diagnosis with the other immune findings.  Our current plan is to instigate a trial of corticosteroids and if this is successful to consider treating as Haemophagocytic syndrome.
 
We are considering a systemic granulatous inflammatory syndrome and are wondering if she may develop the granulomata/uveitis later.
 
Any suggestions would be most welcome.
 
Thank you.
 
Dr Brynn Wainstein.        
 
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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