[CIS PIDD] [cis-pidd] ?SCID with severe neutropenia

[CIS-PIDD]

I wanted to reach out about a patient who came to us because of positive
newborn screen and an original TREC level of 3.  She is now  1 month old
with presumed SCID.



Flow showed (repeated and confirmed results):

CD3-80

CD4-29

CD8-19

CD19-75

CD16/56-460

CD45/4/RA-4 (15%)

CD45/4/R0-22 (77%)

CD45/8/RA-11 (57%)

CD45/8/R0-6 (31%)

56% of CD4+ cells and 9% of CD8+ are positive for HLA-DR.



ALC has remained low (500-700 depending on day) and absolute neutrophil
count is *zero*, she has not responded to G-CSF (2 different occasions).
She also has a very faint erythema and scaling (honestly not that bad at
all and nothing like omenn I have seen, but also definitely not normal
skin).  IgE is <2 and eosinophils have been normal.  No lymphadenopathy and
no hepatosplenomegaly.  She had spectratyping that came and showed
oligoclonal/non-Gaussian distribution, polyclonal expression in 3 families
of TCR V beta repertoires.   Proliferation was normal to PHA for % of
CD45-53.5% (normal>49.9) and CD3-83.1 (normal>58.5), not enough cells for
PWM.



Genetic testing showed a heterozygous variant of unknown significance in
PRKDC c.5446C>T (p.R1816C).  Not present in ExAC and predicted to be
deleterious, but heterozygous.  Also tested and no pathogenic variants in
ADA, AK2, ATM, CD3D, CD3E, CD3Z, CORO1A, DCLRE1C, DOCK8, FOXN1, IL2RG,
IL7R, JAK3, LIG4, NHEJ1, ORAI1, PNP, PTPRC, PRKDC, RAC2, RAG1, RAG2, RMRP,
STIM1, TBX1, ZAP70.



Skin biopsy

Examination of the biopsy reveals orthokeratosis and a relatively
unremarkable epidermis overlying a mildly dense superficial and mid dermal
periadnexal and interstitial infiltrate composed of lymphocytes,
histiocytes, scattered neutrophils and rare eosinophils. To better evaluate
the infiltrate, immunohistochemical stains were performed. The infiltrate
is composed predominantly of CD20 positive B cells. Very rare scattered CD3
positive T-cells are present, with retention of CD5 and CD7 expression. The
CD4 to CD8 ratio is within normal limits; however, very few T-cells are
present. C25 and CD30 are negative. The Ki-67 proliferative index is
approximately 30% within the infiltrate. Neither fungal microorganisms nor
basement membrane changes are seen with interpretation of a PAS
histochemical stain.



Overall, the findings are relatively mild and not entirely specific. Given
the composition of the infiltrate, we considered the possibility of a
dermal hypersensitivity reaction, such as urticaria, a drug eruption, or an
arthropod bite eruption; however, this does not seem to fit the clinical
impression. We also considered the possibility of a viral exanthem. The
findings present in the current biopsy do not show an increased population
of activated T-cells, as can be seen in Omenn syndrome. These findings are
best interpreted in correlation with physical findings, clinical history,
and the results of additional studies, as clinically indicated

We just got the results on genetic testing back today and are attempting to
figure out the significance (if any) of the PRKDC variant.  Obviously only
1 potentially deleterious variant was identified in an AR condition.

Thank you everyone for any help/assistance with this difficult case.  Have
a great weekend
Nick

-- 



Nicholas Hartog, MD


Allergy/Immunology


Assistant Professor


Michigan State University College of Human Medicine



C: 608-347-1856

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