[PAGID] Ommen syndrome or something else?

[Howard M Lederman]

Gigi,

Thanks for your helpful comments.  

We did not have the opportunity to test T cells for Ag responses.  No T cell infiltrates in tissues.  No manifestations of auto-antibodies, so we never had a reason to test for them

We have a fibroblast line, and can certainly send cells or DNA to Bresica if it is OK with Silvia.


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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----- Original Message -----
From: "Notarangelo, Luigi" <Luigi.Notarangelo at childrens.harvard.edu>
Date: Thursday, February 25, 2010 3:41 pm
Subject: Re: [PAGID] Ommen syndrome or something else?
To: "pagid at list.clinimmsoc.org" <pagid at list.clinimmsoc.org>
Cc: silvia giliani <silvia.giliani at gmail.com>, Ada Hamosh <ahamosh at mail.jhmi.edu>, Aida Bytyci <abytyci1 at jhmi.edu>



> Hi Howard:

>  

>  The presence of a significant number of B cells argues against 

> defects in V(D)J recombination, which - when causing Omenn - usually 

> cause a B-negative variant of the disease.

>  I assume NK cells were present (based on sum of CD3 and CD19 

> percentage). If so, I would explore hypomorphic IL7R defects first. 

> CD3 chain defects have not been associated with Omenn yet, however 

> that is also a possibility. The phenotype with extremely reduced CD8 

> makes in fact think of ZAP-70 deficiency but it is true that mitogens 

> are too good for a ZAP-70 deficiency.

>  

>  Both my group and Chaim Roifman have reported on patients with RMRP 

> mutations who lacked CD8+ T cells, and Omenn syndrome has been 

> previously described in patients with RMRP mutations. Importantly, 

> some of these patients with RMRP mutations and severe CD8 lymphopenia 

> did NOT have the skeletal features of cartilage hair hypoplasia (see 

> Kavadas et al, JACI 2008). This possibility should also be explored.

>  

>  What is rather unusual for Omenn is the relatively high proportion of 

> naïve T cells (in almost all cases of true Omenn I have seen, 90% or 

> more of the T cells were CD45R0+). Also, the presence of Hassall's 

> corpuscles in the thymus (albeit in reduced number) is not typical of 

> Omenn. Was response to antigens tested before death? Were there any T 

> cell infiltrates in target tissues at autopsy? (this would be a sine 

> qua non in Omenn). Lastly, any evidence for autoantibodies and true 

> autoimmune manifestations?

>  

>  

>  Silvia Giliani, from my former group in Brescia, would be able to 

> analyze Omenn-associated gene defects and perhaps use homozygosity 

> mapping first to rule out some of them. I am cc:ing her here. Feel 

> free to contact her and/or me, if you wish.

>  

>  Best regards

>  

>  Gigi

>  

>  

>  Luigi D. Notarangelo, M.D.

>  Jeffrey Modell Chair of Pediatric Immunology Research in Boston

>  Director, Research and Molecular Diagnosis Program on Primary Immunodeficiencies

>  Division of Immunology, Children's Hospital

>  Professor of Pediatrics and Pathology, Harvard Medical School

>  Karp Building, 9th floor, Rm 09210

>  1 Blackfan Circle

>  Boston, MA 02115

>  USA

>  

>  (tel) (617)-919-2276

>  (fax) (617)-730-0709

>  

>  

>  Secretary: Luisa Raleza

>  email: luisa.raleza at childrens.harvard.edu

>  

>  

>  

>  

>  On 2/25/10 2:54 PM, "Howard M Lederman" <hlederm1 at jhmi.edu> wrote:

>  

>  I saw a puzzling pt with diffuse congenital erythroderma/ichthyosis 

> (colloidion baby?); pseudomonas sepsis at age 2 months; died at age 3 

> mos with disseminated CMV (lungs, liver, lymph nodes). Oriental 

> consanguinious parents.

>  

>  ALC about 2500; CD3 59%, CD4 57% (1318/cu mm), CD8 2%, CD19 19%

>  

>  74% of CD3 cells were CD45RO+/HLADR+

>  

>  76% of CD3 cells were CD45RO+/CD25+

>  

>  Mitogens: Unstim 265; PHA 35,120; ConA 39,275

>  

>  IgG 465, IgA 19, IgM 17, IgE 10,210; multiple oligoclonal bands on IFE

>  

>  At autopsy - hypoplastic thymus with few Hassall's corpuscles; lymph 

> nodes depleted of lymphocytes

>  

>  The low CD8 count made me think of Zap-70 deficiency but I thought 

> that her mitogen responses were too good to fit.

>  

>  Otherwise, the picture looked like Ommen syndrome, but the RAG-1 and 

> RAG-2 mutation sequences were normal.

>  

>  

>  

>  We would like to get a genetic dx since this is a young family who 

> wishes to have more children.

>  

>  Does anyone have a suggestion as to the next genes to sequence?

>  

>  

>  

>   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

>  

>  WARNING: E-mail sent over the Internet is not secure.

>  Information sent by e-mail may not remain confidential.

>  

>  DISCLAIMER: This e-mail is intended only for the

>  individual to whom it is addressed. It may be used only in accordance 

> with applicable laws. If you received this e-mail by mistake, please 

> notify the sender and destroy the e-mail.

>  

>  

>  

>  

>