[CIS PIDD] [cis-pidd] Hyper IgM syndrome?

Tue Aug 16 10:46:51 EDT 2016

Hi Elena,
Regarding poor NEMO coverage by WES - you might get better coverage by using a different algorithm to map/align reads since the presence of the NEMO pseudogene can make some of your reads ambiguous. Alternatively, you can sometimes find mutations that were missed by WES by sequencing cDNA. I’d be happy to send you our protocol or have my lab do this.

Eric

Eric Hanson, MD
Assistant Clinical Investigator
Head, Immunodeficiency and Inflammation Unit
Autoimmunity Branch, NIAMS
National Institutes of Health
Bldg 10 Rm 13C103
Bethesda MD 20892-1930

office: 301-827-9401
lab: 301-496-0676
fax: 301-480-2393
cell: 240-271-1706

Lab link: 
http://goo.gl/8nlhsF

On 8/15/16, 4:06 AM, "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org> wrote:

>Hi Elena, 
>
>And if CTLA4, LRBA, PIK3CD, PIK3R1 all seem normal, remember that WES does not show intronic mutations or complex rearrangements, these have been found in some and I would not be surprised if eventually in all of them. 
>
>And if nothing there either, "CVIDs" with prominent lymphadenopathy can have this phenotype. 
>
>(A young boy with early-onset hypogamma and hyper-IgM phenotype sounds monogenic (known or unknown form) anyhow...Other PIK3 complex genes?)
>
>Keep us informed, Elena?
>
>ATB
>
>Mikko
>
>-----Alkuperäinen viesti-----
>Lähettäjä: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org] 
>Lähetetty: 13. heinäkuuta 2016 12:00
>Vastaanottaja: CIS-PIDD <cis-pidd at lyris.dundee.net>
>Aihe: Re: [cis-pidd] Hyper IgM syndrome?
>
>CTLA4 looked at in detail?
>We have initially missed patients with heterozygous whole exon or whole gene deletions in CTLA4 gDNA.
>Same applies for comp het deletions in LRBA...
>Best, Bodo
>
>****************************************
>Univ.-Prof. Dr. med. B. Grimbacher
> 
>Scientific-Director
>CCI-Center for Chronic Immunodeficiency
>UNIVERSITÄTSKLINIKUM FREIBURG
>Tel.: 0761 270-77731  Fax: -77744
>Breisacherstraße 115, 79106 Freiburg
>bodo.grimbacher at uniklinik-freiburg.de
>www.uniklinik-freiburg.de/cci
> 
>and 
> 
>Consultant Immunologist
>Institute of Immunity & Transplantation
>Dept of Immunology
>Royal Free Hospital
>UNIVERSITY COLLEGE LONDON
>Pond Street
>London NW3 2QG
>b.grimbacher at ucl.ac.uk
>
>www.centreforimmunodeficiency.com
>
>
>
>
>Am 12/07/16 17:33 schrieb "CIS-PIDD" unter <cis-pidd at lists.clinimmsoc.org>:
>
>>Dear colleagues,
>>
>>I am writing to ask you for your opinion about a challenging case.
>>
>>Our patient is a 14yo boy who was healthy until the age of 9yo when he 
>>had two episodes of ITP episodes treated with steroids, IVIG, and 
>>rituximab.  Then this year, he was hospitalized for fever with ITP,
>>Coombs+ anemia, weight loss, pulmonary nodules on chest CT, and
>>significant splenomegaly.  He was treated with IV antibiotics, and 
>>slowly improved, without any immuno suppression.  Immunoglobulin levels 
>>demonstrated IgA <5, IgG <25, IgM 1357 (last rituxtimab dose 4 years 
>>ago). Lymph node biopsy demonstrated follicular hyperplasia with 
>>predominant primary follicles (no polarization), and increased IgM+ 
>>lymohoplasmacytic cells.  No evidence of malignancy nor plasmactyosis.
>>BM biopsy demonstrated mildly hypo cellular marrow (70%) with active 
>>trilineage hematopoiesis.  Normal T cell, NK, and total B cell numbers, 
>>but decreased (close to zero) isotope switched B cells (CD19+CD38+IgM-,
>>CD19+CD27+IgM-IgD-).  Normal Treg cell numbers (foxp3 stain).  
>>CD19+CD27+Lymphocyte
>>stimulation with normal mitogen and tetanus response (mildly decreased 
>>ConA, but otherwise normal). A battery of infectious studies all 
>>yielded negative results (EBV, CMV, bacterial cx, PCP, fungal cx, 
>>mycobacterial cx).
>>
>>WES sent at this point, and started on IgG replacement, with no other 
>>immunomodulator. Splenomegaly significantly improved, no fevers, normal
>>CBC, still some fatigue, slowly regaining weight.   3 months later,
>>repeat immunoglobulins demonstrate IgG 207, IgA<10, IgM 340.  WES 
>>results
>>(GeneDx) demonstrate het mutations for PKLR (pyruvate kinase 
>>deficiency), VPS13B (Cohen syndrome), and ANK1 (hereditary 
>>spherocytosis).  Given his IgM has almost normalized with only IgG 
>>supplementation, this is unlikely HIGM I think. CD40/40L,UNG, AID, IKBa 
>>coverage was pretty good. NEMO coverage not so good (26%).  He however 
>>does not many any of the physical exam features, and does not have any 
>>GI issues.  None of the mutations founds are consistent with his phenotype, and they are only heterozygous.
>> 
>>
>>I¹m facing a diagnostic dilemma at this point.  My original thought of 
>>HIGM seems to have gone out the window, any other suggestions?
>>
>>Thanks,
>>
>>Elena Hsieh, MD
>>Department of Immunology and Microbiology Department of Pediatrics, 
>>Division of Allergy and Immunology University of Colorado, Denver
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