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

[Ashish Kumar]

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 [mailto:troy.torgerson at seattlechildrens.org] 
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
[mailto: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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