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

[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 50th percentile, her height is <3rd 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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