[PAGID] FW: ? Granulomatous Angiitis

[Jack Bleesing]

The article that I think explains this patient (especially if RAG is to
be considered) = 

N Engl J Med. 2008 May 8;358(19):2030-8.  Links
An immunodeficiency disease with RAG mutations and granulomas.
Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider
DT, Manfras B, Pannicke U, Willemze R, Knüchel R, Göbel U, Schulz A,
Borkhardt A, Friedrich W, Schwarz K, Niehues T.
Department of Pediatrics and Adolescent Medicine, University Hospital
Ulm, Ulm, Germany.
We describe three unrelated girls who had an immunodeficiency disease
with granulomas in the skin, mucous membranes, and internal organs. All
three girls had severe complications after viral infections, including
B-cell lymphoma associated with Epstein-Barr virus (EBV). Other findings
were hypogammaglobulinemia, a diminished number of T and B cells, and
sparse thymic tissue on ultrasonography. Molecular analysis revealed
that the patients were compound heterozygotes for mutations in
recombination activating gene 1 or 2 (RAG1 or RAG2). In each case, both
parents were heterozygous carriers of a RAG mutation. The mutations were
associated with reduced function of RAG in vitro (3 to 30% of normal
activity). The parents and one sibling in the three families were
healthy. Copyright 2008 Massachusetts Medical Society.


Regards,

JB

---------------------------------------------------------------------------
Jack J.H. Bleesing, M.D., Ph.D.
Associate Professor of Pediatrics
Cincinnati Children's Hospital Medical Center
Division of Bone Marrow Transplantation & Immune Deficiency
3333 Burnet Avenue, MLC 7015
Cincinnati, OH 45229
513-636-4266 (phone)
513-636-3549 (fax)
Jack.Bleesing at CCHMC.org
http://www.cincinnatichildrens.org/immunodeficiencies/

>>> "Vogler, Larry B" <lvogler at emory.edu> 09/30/09 5:24 PM >>>

Thanks very much for your all of your comments so far.
I do not currently have the answers to all of the questions posed, but
will try to obtain them.
We will definitely look into a defect in V-D-J recombination. I don't
believe that she had an SPEP run and her biopsy tissue was not stained
for immunoglobulins, CHOP did not look at TLRs.  Our pathologist states
that the predominant cell type in the lesions is histiocytes, with some
neutrophils and relatively few eosinophils and lymphocytes.  The patient
has a normal head size and neurological development. I will keep you
posted on the results of further investigations.
Larry Vogler

From: pagid-bounces at list.clinimmsoc.org
[mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of
pagid at list.clinimmsoc.org
Sent: Wednesday, September 30, 2009 9:41 AM
To: Vogler, Larry B; pagid at list.clinimmsoc.org
Subject: Re: [PAGID] FW: ? Granulomatous Angiitis
Importance: Low

A couple of questions on the IgG- I assume there is no monoclonal spike
?  What is her EBV status ?

Then: Was the lesion stained for Ig's ?  Have you or CHOP or someone
done a TLR screen ?

Melvin Berger, M.D., Ph.D.
Adjunct Professor of Pediatrics and Pathology
Case Western Reserve University
phone 216 844 3237

Director, Jeffrey Modell Center for Primary Immune Deficiencies
Division of Allergy-Immunology
Rainbow, Babies and Children's Hospital
University Hospitals of Cleveland
RB&C Rm 504, MS 6008B
11100 Euclid Ave.
Cleveland, OH 44106

________________________________
From: pagid-bounces at list.clinimmsoc.org on behalf of Vogler, Larry B
Sent: Tue 9/29/2009 5:53 PM
To: pagid at list.clinimmsoc.org
Subject: [PAGID] FW: ? Granulomatous Angiitis
[cid:~WRD000.jpg]

I would very much appreciate any help that you may provide in the
diagnosis and management of this patient.

The patient is a 10 year old East Indian girl with a normal birth.  She
had some episodes of pharyngitis and gastroenteritis after age 4 months
and was hospitalized at age 10 months at Children's Healthcare of
Atlanta-Egleston with well-confirmed adenoviral hepatitis. At 19 months
in 12/00 she had an episode of IgG auto-immune hemolytic anemia. In
12/03 she had pneumonia and in 3/05 bronchitis anan ear drum perforation in 5/06 and was diagnosed with asthma in 4/08.
In 11/08 she was noted to have growth retardation and nail clubbing.  A
chest CT showed extensive bronchiectasis. In 1/09 she developed swelling
of her left elbow and left ankle associated with tender subcutaneous
nodules. An MRI showed lytic lesions in the distal humerus and increased
marrow signal in the proximal left radius.
She has had high ESRs (118) and the following additional labs: WBC 4.0:
69% segs, 17% lymphs, 7% monos, 7% eos, Hgb 9.3, platelets 234. IgG
2280, IgA 60, IgM 92, IgE <2, CH50 51. CD4 lymphocytes 27% (absolute ct.
 295), CD8 9% (101), CD 19 14% (164), CD 16/56 37% (420). Good responses
to PHA and Con A in vitro, normal NK killing in vitro and normal
neutrophil oxidative burst.  ANCA was negative, ANA + 1:160, ACE 20
(nl).  TB skin test negative, and negative routine, fungal and AFB
cultures and serologies for Brucella, Bartonella, Histoplasma and HIV.
She has been evaluated at MCG, CHOP and Emory. A biopsy of an elbow soft
tissue lesion on 5/11/09 was interpreted by our pathologist as showing
necrotizing angiocentric granulomatous inflammation with granulomatous
angiitis of small to medium-sized arterioles. A recent bronchoscopy 
showed signs of chronic bronchial inflammation but no organisms. An
abdominal ultrasound showed modest splenomgaly with normal echogenicity
and a brain MRI was normal.  A recent ophthalmology exam revealed no
uveitis or retinal lesions.  Attached are photos of the skin lesions and
histopathology.
We believe that she has necrotizing sarcoid granulomatosis as described
in the following Pub Med articles: PMID 17377369, 12823717, 12784179,
12687600, 10232451, 8092646.  However, this is not certain and we are
reluctant to immunosuppress this young girl with low lymphocyte numbers
if other diagnoses are likely.

Thanks for your thoughts.
Larry


Larry B. Vogler, M.D.
Director, Division of Rheumatology and Immunology
Department of Pediatrics
Emory University
2015 Uppergate Drive
Atlanta, GA 30322
phone: 404-778-2400
fax: 404-727-3757



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