[CIS PIDD] [MARKETING][cis-pidd] CMV, CD4 lymphopenia, adenopathy, nephritis....

[Seppänen Mikko]

Hi David,
at “this advanced” age, whenever there is B- and NK-penia (+/- CD4 penia) I would rule out GATA2 first. First sequencing and then - if no mutations found - GATA2 mRNA level check to rule out GATA2 haploinsufficiency.
In our material, monocytopenia and even DC-penia often seem to occur later in the disease than B- and NK-penias, and in rough testing NK function seems in it to be rather normal (but low counts of course). Check these as well of course, but do not rule out GATA2 if still normal.
Mass lesions with EBV positivity as well as disseminated CMV have been reported in GATA2, thus this mass-lesion might be compatible with GATA2?
Though the interstitial nephritis sounds like it could have been provoked by e.g. NSAIDs for fever, experimentally low GATA2 mRNA has been linked with glomerulonephritis. Swelling: lower limbs (Emberger?)?
At least in Finland, though we in control WESes (n >3200) do not seem to have an excess of any pathogenic GATA2 mutations, GATA2 def seems to be the second most common later-onset PIDD after CVID. Thus I would next think of other options only after GATA2 has been definitely ruled out.
That being said, there are of course a number of other PIDD gene mutations possible, but those I would then pursue with clinical WES, and if the insurance company disagrees, “they sure do not understand simple math” ( ;=O  :=) )
ATB
Mikko


oyl Mikko Seppänen
Harvinaissairauksien yksikkö (HAKE), HUS

Mikko Seppänen, MD, PhD, Associate professor
Specialist in Internal Medicine and Infectious Diseases
Chief, Rare Disease Center, Helsinki University Hospital (HUH)
Children’s Hospital, P.O.Box 280
FI-00029 HUS
FINLAND
&
Senior Consultant (PIDD)
Adult Immunodeficiency Unit
Inflammation Center, HUH

phone +358 9 47180201
GSM +358 50 4279606
fax +359 9 47174703


Lähettäjä: David Buchbinder [mailto:dbuchbinder at CHOC.ORG]
Lähetetty: 10. kesäkuuta 2015 8:19
Vastaanottaja: CIS-PIDD
Aihe: [MARKETING][cis-pidd] CMV, CD4 lymphopenia, adenopathy, nephritis....

Dear Colleagues,

I wanted to see if anybody has any suggestions with respect to the case below with respect to additional diagnostic work up or suggestions for targeted sequencing for some of the more novel immune dysregulation syndromes (e.g. PI3KCD, etc.).

We have a 7 year old previously healthy male who originally presented with abdominal pain and pancreatitis.

Imaging documented a lung nodule retroperitoneal mass as well as diffuse mesenteric  and retroperitoneal adenopathy.

Pathologic examination documented CMV inclusions on the lung biopsy and retroperitoneal mass.  He was treated with ganciclovir.  There was a lymphocytic infiltrate present (largely T cells) and some eosinophils.  No IgG4 plasma cells were noted.   He developed chylous ascites and chylothorax which resolved.

Most recently he came in with fevers, night sweats, and swelling.   Due to concerns of renal insufficiency a biopsy was obtained.  It demonstrated acute tubulo-interstital nephritis.  The intersitium demonstrate lots of lymphocytes, macrophages, eosinophils, and few plasma cells.  Immunostains for CMV (and EBV) were negative.  We also biopsied the mesenteric / retroperitoneal adenopathy.  There was lymphohistiocytic infiltrate (largely T cells and histiocytes).  No malignancy.

His immunoglobulin levels are relatively unremarkable - IgE 229, IgA 132, IgG 1164, IgM 38 although his IgM is a bit low.
His lymphocyte panel demonstrates a slightly reduced number of B cells 146 / uL and NK cells 56 / uL.  His CD3 and CD8 numbers are fine.
His CD4 numbers are low at 180 / uL.  Naïve CD4 and  CD8 percentages are low  (8.1% and 23% respectively).    CD4 cells have slightly decreased expression of TCR alpha/beta (80%).
Mitogens were generally normal with some decreased Ag specific responses.
NK cytotoxicity was normal.
Some limited genetic analysis (e.g. NGS SCID panel) was done and negative.

Thanks as always....

Dave Buchbinder
CHOC Children's - UC Irvine



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