[CIS-PAGID] case

[Torgerson, Troy]

Jen,

You didn't mention whether the identified IKBKG mutation was heterozygous but I am assuming that it is.  Your array CGH confirmed that she is really a "She" so a heterozygous IKBKG (NEMO) mutation would be a stretch as the cause of these symptoms unless she had a deletion on one allele and mutation on the other but you didn't mention that the array CGH noted any deletions on the X-chromosome.

An IkBalpha mutation seems far more likely since these are autosomal dominant - cases usually arise sporadically because of a new mutation.  You only need to mutate one of the 2 key serine residues (S32 or S36) required for phosphorylation in order to create a dominant–negative, non–degradable IkBa that very effectively shuts down TLR signaling.  Patients are often lymphopenic but not all.  A simple flow assay can quickly determine whether IkBa is degraded upon activation (a good functional screen for both IkBa and IKBKG mutations) and sequencing of IkBa can confirm a mutation.  Both are available as clinical tests.

Best,

TT

Troy R. Torgerson, MD PhD

Assistant Professor, Pediatric Immunology/Rheumatology
University of Washington School of Medicine
1900 9th Ave., C9S-7
Seattle, WA  98101-1304

Tel:  (206) 987-7317
Fax:  (206) 987-7310

Director, Immunology Diagnostic Laboratory (IDL)
Seattle Children's Research Institute
1900 9th Ave., C9S-7
Seattle, WA  98101-1304

Tel:  (206) 987-7IDL (-7435)
Web:  www.seattlechildrens.org/IDL








From: "Heimall, Jennifer" <heimallj at email.chop.edu<mailto:heimallj at email.chop.edu>>
Reply-To: <pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>>
Date: Tue, 10 Jan 2012 16:50:34 -0500
To: "pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>" <pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>>
Subject: [CIS-PAGID] case

I would appreciate your thoughts on this difficult case:

My patient is 21 month old Caucasian female born to unrelated parents who has had transfusion dependant macrocytic anemia of unknown etiology since November 2010.  She was found to have a granuloma on bone marrow biopsy in spring 2011, cultures were negative.  She also has eczema and frequent loose stools with poor weight gain.  From an infectious standpoint she has has 1-2 episodes of otitis but is otherwise well. However she is an only child and cared for at home by her mother with limited exposures.

As part of the evaluation for a possible immunodeficiency, TLR functional assay was obtained and was remarkable for decreased responses to TLR 1-8 performed twice.  DHR was normal.  Flow: CD3 3221, CD4 2577, CD8 501, CD20 1512, CD16/56 243.  Total IgG 885, IgA 61 and IgM 61, IgE 96. Diptheria 2.59, Tetanus 0.28
She had skewed X-inactivation on a sample performed by a research laboratory, but repeat x inactivation studies by a commercial lab showed random inactivation.
Telomere length assessment has been normal in lymphocyte and granulocytes.  Cytogenetics microarrary revealed a normal female (1-22, X)x2
Mutation analysis performed by a commercial lab of IKBKG showed a variant c. 1056-18 C>T that is reported to be undetermined significance but predicted to lead to an intronic mutation.

There is consideration for transplant due to the anemia due to her young age and iron overload issues.

Thanks for any thoughts regarding further evaluation/treatment…
Jen


Jennifer Heimall, MD
The Children's Hospital of Philadelphia
Allergy/Immunology Attending Physician
3550 Market Street
3rd Floor
Philadelphia, PA 19104



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