[PAGID] Puzzling case of hypergammaglobulinemia with absence of antibody responses

[dmvascon at usp.br]

Dear Dr. Lederman

This is really a very interesting and intriguing patient. Despite  
trying a lot to associate all features I couldn't get a perfect  
diagnostic hypothesis.
Thinking about PIDs, I could think about transcobalamin II deficiency,  
that could explain the antibody deficiency (but there is no  
hypogammaglobulinemia),  neutropenia and neurological symptoms; I  
noted T cell lymphopenia with more pronounced CD8 depletion. Do you  
have B and NK cell counts? Dr. Sullivan's hypothesis is very  
interesting and might explain the Ig oligoclonality. Is there any  
characteristic feature (facies, microcephalia, pigmentation  
disturbances) that could drive to the diagnosis? I was thinking in the  
possibilities of ICF, Bloom's, LIG4 or Cernunnos deficiencies (or even  
RAG 1/2 and Griscelli type 2). PNP is another very important  
hypothesis but it was already discarded.
On the other hand, we might think about infectious diseases that could  
lead to neurological symptoms and oligoclonality, such as Lyme  
disease, measles, herpes virus etc. Moreover I think that could be  
interesting to test for autoimmunity (primary or associated to any  
infection) and even lymphoproliferative diseases.
Nevertheless we could not discard the possibility that corticosteroids  
are a main factor in the development of the clinical manifestations of  
the patient, such as lymphopenia, low proliferative responses to  
mitogens (temporary), hypoadrenalism and even susceptibility to  
infections.

I am really curious about this case and I hope that this discussion  
could help.

All the best,
Dewton

Dewton de Moraes Vasconcelos
University of São Paulo Medical School


Citando Howard M Lederman <hlederm1 at jhmi.edu>:


> I am evaluating a 20 month old girl with a perplexing combination of  

>  findings, and could use some help:She was a full-term infant who   

> began having recurrent otitis media at 10 months of age. For unclear  

>  reasons, she was treated with 5 days of prednisone + antibiotics  

> for  each OM.  At age 12 months, she stopped standing, putting  

> weight on  her legs, and cruising.  She had normal brain MRI, EMG,  

> and nerve  conduction velocity tests.  Shortly after, she was  

> treated with  Decadron on 3 occasions within 2 wks for croup.  The  

> following week,  she developed stridor, and was intubated with  

> findings of laryngeal  and subglottic swelling.  She was treated  

> with pressors, blood  transfusion, and GM-CSF.  During her  

> hospitalization, a trachea  culture was positive for Pseudomonas and  

> Enterobacter.  Blood  cultures were negative.  She developed  

> candidal esophagitis and C.  difficile diarrhea. During her  

> hospitalization, she was found to  have hepatosplenomegaly, still of  

> unknown etiology. She was found to  have a drenal insufficiency,  

> presumed to be secondary to steroid  use, and was started on  

> replacement therapy.

>

> While hospitalized in 05/2008, she was evaluated for   

> immunodeficiency. She had normal immunoglobulin levels (IgA 291   

> mg/dL, IgG 1270 mg/dL, and IgM 372 mg/dL).  She had normal adenosine  

>  deaminase (67.3 nmol/h/mg) and purine nucleoside phosphorylase  

> (1730  nmol/h/mg) levels.  She had diminished lymphoproliferative  

> responses  to PHA (33% normal control), concanavalin A (6% normal  

> control), and  pokeweed mitogen (58% normal control).  She had low  

> percentages and  numbers of CD3 (31%; 294/cu mm), CD4 (24%; 223/cu  

> mm) and CD8 (7%,  65/cu mm) T-lymphocytes.

>

> When I first saw her last month, she had normal responses to T-cell   

> mitogens (unstimulated 318 cpm, Phytohemagglutinin A 77,979 cpm,   

> Concanavalin A 29,606 cpm), and negative FISH for 22q11 deletions.    

> She had a borderline low white blood count (5850/cu mm) with 63%   

> lymphocytes (3710/cu mm).  She had low percentages of CD3 (35%), CD4  

>  (29%; 998/cu mm) and CD8 (5%) T lymphocytes.  Despite the high   

> levels of IgG (and IgA), she had no detectable IgG Ab to previously   

> administered vaccines, nor to a subsequent booster dose of Prevnar.   

>   PCR tests for HIV, CMV and EBV were negative.  Ferritin normal (17  

>  ng/mL), trigylcerides slightly high (169 mg/dL).  Her IgG and IgA   

> levels have increased.  IFE shows multiple bands of restricted   

> electrophoretic mibility in IgG, IgA, kappa and lamda lanes

> I am anxious for ideas to explain all of this.

> Howard

> Howard M. Lederman, M.D., Ph.D.

> Professor of Pediatrics, Medicine and Pathology

> Division of Pediatric Allergy and Immunology

> Johns Hopkins Hospital - CMSC 1102

> 600 N. Wolfe Street

> Baltimore, MD 21287-3923

> Phone: 410-955-5883

> Fax: 410-955-0229

> Email: Hlederm1 at jhem.jhmi.edu

>

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