[CIS PIDD] [cis-pidd] 2 year old girl with possible SCID

[Dr. Carsten Speckmann]

Normal naive cells and proliferation argue against a classic (S)CID.
However, the clinical presentation with susceptibility to bacterial/viral infections and immune dysregulation (plt?/spleen) is suspicious...

Maybe the defect is more subtle - e.g. a problem of T cell activation.
Can you check for "early T cell activation": e.g. CD25, CD69 upregulation? Any signs for ectodermal dysplasia (e.g. teeth)? Ca Flux?

How good was the coverage for the VDJ defect genes in the panel diagnostics? RAG1/2, Artemis really excluded?
I would also add radiosensitivity to the diagnostic programm.

Is there g/d T cell expansion?
(which we frequently observe in our prospective natural history study on CID - www.pcid-study.org)

What was the nature of thrombocytopenia? Autoimmune?

We have seen T-B-, hypogamma and transient (non autoimmune) thrombocytopenia during viral infection as first presentation of Dyskeratosis congenita (without other presentation of DC at this stage).
Naive Ts and proliferation are frequently normal in these children: telomeres?

Based on the reported clincal problems of your patient, I would consider SCT as a possible (not mandatory) therapeutic options (but certainly search for a donor to be prepared in case of clincial aggravation).

Kind regards, Carsten

-- 
Carsten Speckmann, MD
Consultant Immunologist
Center for Chronice Immunodeficiency- CCI
and Center of Pediatrics
University Freiburg Medical Center
Germany

phone: +49 (0)761-270 43010
mail: carsten.speckmann at uniklinik-freiburg.de
web: www.cci.uniklinik-freiburg.de


Am 17.08.13 00:45, schrieb Boyce, Thomas G., M.D.:

>

> I would like input on a patient I saw for the first time in clinic 

> last week with significant pan-T cell lymphopenia, modest B cell 

> lymphopenia and normal total NK cell count.  Total ALC (CD45 lymph 

> count) = 370 cells/uL.

>

> The questions are:

>

> 1. How would you go about further classifying / diagnosing her SCID?

>

> 2. Would you do whole exome sequencing?

>

> 3. Would you plan for a BMT now or follow her function over time 

> before deciding? (she has one older sibling who has not be HLA tested)

>

> This is a 2 year old girl, born at term. At 1 month of age she 

> developed a facial rash, treated with antibiotics.  At 4 months of 

> age, she developed RSV pneumonia, hospitalized for 6 days, no 

> mechanical ventilation required.

>

> She developed recurrent otitis media and had an episode of 

> mastoiditis, requiring mastoidectomy.

>

> She has had several episodes of CXR confirmed cases of pneumonia with 

> fever and cough.  She responded well to antibiotics. BAL in Dec 2012 

> grew adenovirus and H. flu (not type b).

>

> She received live rotavirus vaccines as well as varicella and MMR 

> vaccines at 12 months of age and tolerated them fine.

>

> At 18 months of age, she developed thrombocytopenia, with platelets as 

> low as 5000.  Bone marrow biopsy at that time was normal, no evidence 

> of malignancy.  Immunoglobulins were checked prior to treatment with 

> IVIG, and her IgG was nearly undetectable and IgM and IgA were very 

> low also.  She has been on IVIG since then.  She is also on treatment 

> doses of Bactrim daily.  She has been relatively healthy since those 

> two interventions started.

>

> Her development has been good.

>

> On physical exam: her weight is 50^th percentile, her height is <3^rd 

> percentile.

>

> She is very active, well-appearing.

>

> Spleen is enlarged (3 cm below LCM).  Liver is normal. No adenopathy, 

> although she does have lymph tissue.

>

> Rest of exam is normal.

>

> Previous evaluation elsewhere included the SCID panel at GeneDx, which 

> was negative for mutations in ADA, AK2, CD3D, CD3Z, DCLRE1C, IL2RG, 

> IL7R, JAK3, LIG4, NHEJ1, PNP, RAC2, RAG1, RAG2, RMRP, ZAP70, IKBKG 

> (Nemo) in exons 4-10.

>

> The patient has a heterozygous missense mutation (E429G) in the PTPRC 

> gene encoding CD45.  SIFT indicated this was a tolerated mutation even 

> though Grantham distance was moderate at 98.  MutationTaster called it 

> a polymorphism.

>

> Her eval here shows:

>

> CD3 242

>

> CD4 183

>

> CD8 58

>

> CD19 64

>

> NK 64

>

> These are absolute numbers.

>

> IgA 1

>

> IgM 5

>

> Evaluation of thymic function by TREC and CD4 recent thymic emigrant 

> analysis by flow revealed 5845 copies/million CD3 T cells (>4168 

> copies/million CD3 T cells) and 51% CD4+CD45RA+ T cells and 32% 

> CD4+CD45RO+ T cells (of total CD4 T cells) and 89% CD31+CD4+CD45RA+ T 

> cells of the total CD4+45RA+ population.  These results suggests that 

> despite her T cell lymphopenia she  has adequate #s of naïve T cells 

> (especially in the CD4 compartment).  TCR repertoire diversity 

> analysis revealed normal polyclonal, Gaussian distribution of the TCR 

> Vb families with no evidence of oligoclonality or a skewed repertoire.

>

> >

>

> > Functional T cell studies were as follows:  proliferation to PHA was 

> robust and normal at 85% (>= 58.5%) for CD3+ T cells with excellent 

> cell viability and no evidence of enhanced cell death in culture.  

> Measurement of intracellular cytokines (IL-2, TNF-a, IFN-g) in CD4 and 

> CD8 T cells after PHA and PMA/ionomycin stimulation was also robust 

> and normal and very comparable to healthy control.

>

> >

>

> > B cell subset immunophenotyping showed distinct abnormalities: 

> significant decrease in class-switched memory B cells for age at 0.2% 

> (2-5yrs: mean = 10.9%, range = 4.7-21.2%), substantial increase in % 

> transitional B cells at 78% (mean = 6.3%, range = 3.1-12.3%).  Also, 

> the relative proportion of CD21+ to CD21- B cells was skewed with a 

> notable decrease in the former and 100% of the CD21+ B cells had 

> CD21dim/low expression.

>

> >

>

> > In summary, the patient has a T-B-NK+phenotype with normal T cell 

> function and relatively normal numbers of naïve CD4 T cells and a 

> normal distribution of T cell receptors.  B cell compartment shows 

> several quantitative abnormalities in B cell subsets along with the 

> profound hypogamma (with normal total IgE).

>

> Thomas G. Boyce, MD, MPH

> Pediatric Infectious Diseases and Immunology

> Mayo Clinic

> Rochester, MN 55905

> phone: 507-255-8464

> fax: 507-255-7767

>

> Boyce.Thomas at Mayo.edu

>

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