[PAGID] Ommen syndrome or something else?

[Nicholas Rider]

I like Gigi's idea of homozygosity mapping to potentially exclude  
candidate genes.  We have used this approach extensively to prioritize  
sequencing of candidates for a wide variety of well defined phenotypes  
without a clear molecular etiology (Albeit within an isolated genetic  
community - but could be applicable here given the consanguinity).   
Given the patient's absolute CD4 count (1318/uL) I wonder how likely  
an IL7Ra mutation (even if hypomorphic) would be, especially if they  
have heterozygous calls within or near the IL7Ra gene on 5p13 using  
homozygosity mapping?  Our patients with the IL7Ra mutation are  
homozygous for the IL7Ra T>G variant and present with virtually no CD4  
or CD8 cells; they have normal B-cell (CD19) counts.

Homozygosity mapping and analysis of SNPs through IL7Ra, RAG1/2, RMRP,  
ADA, CHD7, DCLRE1C, LIG4, (others?) known to be associated with an  
Omenn Syndrome phenotype may help exclude candidates and facilitate a  
more efficient molecular workup.  You might be able to narrow the  
search further by comparing microarrays of unaffected siblings with  
the affected child.  Interestingly, you can also use this microarray  
information to 'screen' siblings for HLA identity through the HLA  
region on Ch.6 and also prioritize the high resolution matching  
process to cut costs for the family.

Regarding CHH, so far we have seen a wide variety of lymphocyte  
phenotypes in our patients (n = 31; all homozygous for RMRP 70A>G).   
None have presented with Omenn Syndrome, although this is reported in  
RMRP compound heterozygotes as Gigi mentioned as reported by Chaim  
Roifman.  They generally do not have an isolated low lymphocyte  
subset, but rather low cell counts across the board, especially within  
the T cell compartment.  Most are born with normal growth %iles, and  
all  have skeletal findings associated with CHH at birth.

Best wishes with your patient and family.

Nick

Nicholas L. Rider, D.O.
Clinic for Special Children
535 Bunker Hill Road
Strasburg, PA 17579
Ph:  717-687-9407
Fx:   717-687-9237
nrider at clinicforspecialchildren.org



On Feb 26, 2010, at 3:50 PM, Cowan, Mort wrote:


> Howard, it wasn't clear if you ruled out maternal engraftment or if

> you sequenced ZAP70? IL7Ra would be next, probably, then maybe CD45

> and the CD3 chains. Mort

>

> Mort Cowan

> Sent from my iPhone

>

> On Feb 25, 2010, at 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

>>

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>>

>>

>