[PAGID] Puzzling patient with high normal IgG levels but no antibody responses to vaccines

[HOWARD M LEDERMAN]

Ashish and Troy,

If I understand this correctly, your case is different from ours in that the IgG level was below normal.  Our case has an IgG level >1000 with NO antibody.  If only a few B cells slipped through because of a Btk point mutation, I think I would have expected a low IgG level and perhaps an oligoclonal gammopathy.

Howard M. Lederman, M.D., Ph.D.
Professor of Pediatrics and Medicine
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
e-mail: Hlederm1 at jhem.jhmi.edu


----- Original Message -----
From: Ashish Kumar <kumar036 at umn.edu>
Date: Thursday, July 12, 2007 2:47 pm
Subject: Re: [PAGID] Puzzling patient with high normal IgG levels but no antibody responses to vaccines
To: "'Torgerson, Troy'" <troy.torgerson at seattlechildrens.org>, pagid at list.clinimmsoc.org
Cc: "'Guerrerio, Pamela A'" <pfrisch1 at jhmi.edu>



> The patient Troy mentioned is one that I had discussed on this forum a 

> few

>  weeks ago. This is a 14 mo boy who was perfectly healthy for the 

> first year

>  of his life and then developed recurrent pneumonia - 3 times in 3 months.

>  The 3rd time, it was bilateral and associated with pancytopenia. When 

> I saw

>  him, his total IgG was around 250, with slightly below normal IgA and 

> IgM

>  (not in the agammaglobulinemia range). He did have protective titers 

> to

>  Diphtheria and Tetanus. However, his CD19 and CD20 counts were zero. 

> We

>  rechecked these on fresh samples and they were still 0. As Troy mentioned,

>  he has a BTK mutation but it is a mystery how he made antibodies and 

> had

>  detectable IgG, M and A at the age of 14 months, if he has no B 

> cells. There

>  is no family history to help us out either. I wonder if he is a 

> mosaic for

>  the BTK mutation, which would explain this situation - I don't know 

> if this

>  has been reported before. Another interesting piece in this case is 

> that the

>  absolute lymphocyte count is low - around 1200, and I have not seen 

> this in

>  any other patient with agammaglobulinemia. 

>   

>  Ashish Kumar M.D., Ph. D.

>  Assistant Professor

>  Pediatric Hematology/Oncology/Blood and Marrow Transplantation

>  University of Minnesota 

>    _____  

>  

>  From: Torgerson, Troy [ 

>  Sent: Thursday, July 12, 2007 1:21 PM

>  To: pagid at list.clinimmsoc.org; Ashish Kumar

>  Cc: Guerrerio, Pamela A

>  Subject: RE: [PAGID] Puzzling patient with high normal IgG levels but 

> no

>  antibody responses to vaccines

>   

>  Ashish Kumar has a patient with a similarly unusual story - I don't 

> know if

>  he is on the PAGID listserve but I have cc'd this to him so he can hopefully

>  provide more of the clinical details.  Essentially very low B cell numbers

>  but normal/near normal IgG levels.  We evaluated Btk and expression was

>  normal in platelets by flow cytometry.  When we sequenced the gene we 

> found

>  a previously unreported point mutation in the kinase domain that doesn't

>  show up in any of the SNP databases.  Btk-base shows several point mutations

>  in residues 4-5 base pairs up and downstream but only a nonsense (stop)

>  codon mutation at the same location.  We are not yet sure whether this

>  mutation affects Btk function but this will be a key question.  Since 

> Btk is

>  expressed, it is theoretically possible that this could generate a

>  hypomorphic Btk that could allow a few B cells to slip through development

>  and start churning out antibody in response to activating signals but 

> no

>  specific Ab responses due to the limited number of clones - or NOT??  

> 

>   

>  Best,

>   

>  TT

>   

>  Troy R. Torgerson MD PhD

>  Attending Physician, Pediatric Immunology/Rheumatology

>  Co-Director Immunodeficiency Molecular Diagnostic Lab

>  307 Westlake Ave. North

>  Suite 300

>  Seattle, WA  98109

>   

>  Tel (206) 987-7450

>  Fax (206) 987-7310

>    _____  

>  

>  From: pagid-bounces at list.clinimmsoc.org

>  [ On Behalf Of HOWARD M LEDERMAN

>  Sent: Thursday, July 12, 2007 10:22 AM

>  To: PAGID LISTSERV

>  Cc: Guerrerio, Pamela A

>  Subject: [PAGID] Puzzling patient with high normal IgG levels but no

>  antibody responses to vaccines

>   

>  I have seen pts with low normal IgG levels but poor antibody 

> responses, but

>  this case seems to be way out of my experience.  Are there any specific

>  diagnostic tests that I should be considering?  

>  --------- ----------- ------------- ------------ -------------- ------------

>  ---------- -------------

>  J.S. is a 10-month-old Caucasian male who had no significant infections

>  until 8 mos of age when he developed fever (T=104), lethargy and poor

>  appetite.  A full sepsis workup was conducted and his blood culture grew

>  Pseudomonas aeruginosa in 24 hrs.  His left tympanic membrane spontaneously

>  ruptured during his hospitalization and cultures also grew 

> pseudomonas.   A

>  head CT was normal except for bilateral middle ear opacification.  A 

> chest

>  x-ray was normal.  An abdominal ultrasound was normal.  

>   

>  An immunodeficiency workup showed virtually no CD19+ B-cells (0-2%;

>  11-169/cu mm) with normal numbers of T (90% CD3, 68% CD4 = 4467/cu 

> mm, 21%

>  CD8 = 1349) and NK (6% = 368/cu mm) cells. Serum immunoglobulins were 

> normal

>  for age (IgG 446 mg/dL, IgA 30 mg/dL, IgM 35 mg/dL).

>   

>  J.S. had no other history of infections other than intermittent mild 

> viral

>  upper respiratory tract symptoms.  He has had no skin infections or urinary

>  tract infections.  His growth has been normal. He had received all routine

>  childhood vaccines.

>   

>  Subsequent lab tests have shown INCREASING IgG levels (1020 mg/dL) 

> with low

>  normal IgA (34 mg/dL) and IgM (31 mg/dL). Despite the elevated IgG levels,

>  he had NO detectable IgG antibody to previously administered standard

>  vaccines (<0.2 mcg/ml to 14 tested pneumococcal serotypes, < 0.11 to 

> HIB

>  mcg/ml and <0.10 IU/ml to tetanus).  He had NO increase in IgG Ab after

>  booster doses of Prevnar and Hib conjugate vaccines; tetanus 

> increased only

>  marginally to 0.66 IU/ml.   Repeat T and B cell studies by FACS were

>  essentially the same (CD19 3%; CD20 3.3 %; abs ct 140).  Serum IFE 

> showed no

>  evidence of a monoclonal gammopathy. PCR tests for EBV and CMV were

>  negative.

>   

>    I am open to any and all suggestions.

>  

>  

>  Howard

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

>  Professor of Pediatrics and Medicine 

>  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 

>  e-mail: Hlederm1 at jhem.jhmi.edu 

>  

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